TWI862525B

TWI862525B - Improved synthesis of key intermediate of kras g12c inhibitor compound

Info

Publication number: TWI862525B
Application number: TW108141509A
Authority: TW
Inventors: 安德魯湯瑪斯帕森斯; 布萊恩瑪尼爾可琪瑞; 威廉四世波瓦辛尼; 馬克安東尼卡玻里尼
Original assignee: 美商安進公司
Priority date: 2018-11-16
Filing date: 2019-11-15
Publication date: 2024-11-21
Also published as: EP4234546A2; CA3117221A1; PL3880670T3; CN113015724A; EA202191381A1; IL282682B1; US20200216446A1; US20250368643A1; KR20210093276A; US11299491B2; EP4234546A3; HUE062656T2; JP2020090482A; MA54233A; TW202504899A; IL282682A; DK3880670T3; LT3880670T; WO2020102730A1; CN119638694A

Abstract

The present invention relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound 5M, having the structure, useful for the synthesis of compounds that target KRAS G12C mutations, such as

Description

Improved synthesis of key intermediates for KRAS G12C inhibitor compounds

本發明關於一種改善的有效且可擴展的方法，以製備具有結構的中間體化合物，例如化合物5M，其可用於合成抑制KRAS G12C突變的化合物。The present invention relates to an improved efficient and scalable method for preparing a structured Intermediate compounds, such as compound 5M, can be used to synthesize compounds that inhibit KRAS G12C mutation.

KRAS基因突變在胰臟癌、肺腺癌、結直腸癌、膽囊癌、甲狀腺癌及膽管癌中係常見的。在約25%的NSCLC患者中亦觀察到KRAS突變，並且一些研究已指示，KRAS突變在NSCLC患者中係陰性預後因子。最近，已發現V-Ki-ras2 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突變在結直腸癌中賦予對表皮生長因子受體（EGFR）靶向療法的抗性；因此，KRAS的突變狀態可以在開具TKI療法之前提供重要資訊。總體而言，需要針對胰臟癌、肺腺癌或結直腸癌的患者的新的醫學治療，特別是那些已被診斷出患有以KRAS突變表徵的此類癌症的患者並且包括那些化療後進展的患者。KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma. KRAS mutations are also observed in approximately 25% of NSCLC patients, and some studies have indicated that KRAS mutations are negative prognostic factors in NSCLC patients. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer; therefore, the mutation status of KRAS can provide important information before prescribing TKI therapy. Overall, new medical treatments are needed for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, particularly those who have been diagnosed with such cancers characterized by KRAS mutations and including those who have progressed following chemotherapy.

本發明係關於具有以下化學結構的化合物的改善製備：及其關鍵中間體，即包含以下化學結構的組成物及化合物：；以及。The present invention relates to the improved preparation of compounds having the following chemical structure: and its key intermediates, i.e., compositions and compounds having the following chemical structures: ;as well as .

本發明亦關於製備具有以下化學結構的化合物5M的方法：。The present invention also relates to a method for preparing compound 5M having the following chemical structure: .

本發明亦關於包含以下結構的組成物：。The present invention also relates to a composition comprising the following structure: .

定義縮寫：在本文中可以使用以下縮寫： ACN 乙腈 AcOH 乙酸 aq或aq. 水性 BOC或Boc 三級丁氧基羰基 BuOH 正丁醇 BuOAc 丁醇乙酸酯 cpme 環戊基甲醚 CHCl₃ 三氯甲烷 DCE 1,2-二氯乙烷 DABCO 1,4-二氮雜二環[2.2.2]辛烷 DCM 二氯甲烷 DMA N,N-二甲基乙醯胺 DMAP 4-二甲基胺基吡啶 DME 1,2-二甲氧基乙烷 DMF N,N-二甲基甲醯胺 DMSO 二甲基亞碸 Dppf、DPPF或dppf 1,1’-雙(二苯基膦基)二茂鐵 eq或eq.或equiv. 當量 ESI或ES 電噴霧電離 Et 乙基 Et₂ O 乙醚 EtOAc 乙酸乙酯 EtOH 乙醇 g 公克 h 小時 H₂ 0 水 HPLC 高壓液相層析 iPr 異丙基 IPA 異丙醇 IPAc 乙酸異丙酯 iPr₂ NEt或DIPEA N-乙基二異丙胺（休尼克氏鹼（Hünig’s base）） KHMDS 雙(三甲基矽烷)胺基鉀 KOAc 乙酸鉀 LDA 二異丙基胺基鋰勞森氏試劑（Lawesson’s reagent） 2,4-雙(4-甲氧基苯基)-2,4-二硫代-1,3,2,4-二硫雜二磷雜環丁烷、2,4-雙(4-甲氧基苯基)-1,3-二硫雜-2,4-二磷雜環丁烷 2,4-二硫化物 LC MS、LCMS、LC-MS或LC/MS 液相層析質譜 LG 脫離基（例如鹵素、甲磺酸酯、三氟甲磺酸酯） LHMDS或LiHMDS 雙(三甲基矽烷)胺基鋰 m/z 質荷比 Me 甲基 MeCN 乙腈 MeOH 甲醇 Met 用於交叉偶聯的金屬物質（例如，MgX、ZnX、SnR₃ 、SiR₃ 、B(OR)₂ ） 2-MeTHF 2-甲基四氫呋喃 mg 毫克 min 分鐘 MIBK 4-甲基-2-戊酮 mL 毫升 MS 質譜 MTBE 甲基三級丁基醚 n-BuLi 正丁基鋰 NaHMDS 雙(三甲基矽烷)胺基鈉 NBS N-溴代琥珀醯亞胺 NCS N-氯代琥珀醯亞胺 NMR 核磁共振 Pd₂ (dba)₃ 參(二亞苄基丙酮)二鈀(0) Pd(dppf)Cl₂ ·DCM 與二氯甲烷錯合的[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II) Pd(PPh₃ )₄ 肆(三苯基膦)鈀(0) Ph 苯基 PR或PG或Prot.基團保護基團 rbf 圓底燒瓶 RP-HPLC 反相高壓液相層析 RT或rt 室溫 sat.或satd. 飽和的 SFC 超臨界液相層析 SPhos Pd G3或SPhos G3 甲磺酸(2-二環己基膦基-2’,6’-二甲氧基聯苯基)[2-(2’-胺基-1,1’-聯苯基)]鈀(II) TBAF 四正丁基氟化銨 TBTU N,N,N’,N’ -四甲基-O -(苯并三唑-1-基)脲鎓四氟硼酸鹽 t -BuOH 三級丁醇 TEA或Et₃ N 三甲胺 TFA 三氟乙酸 THF 四氫呋喃 UV XRPD 紫外光 X射線粉末衍射 Definitions Abbreviations: The following abbreviations may be used in this article: ACN Acetonitrile AcOH Acetic acid aq or aq. Water-based BOC or Boc Tertiary Butoxycarbonyl Bu n-Butanol B O Butyl acetate cpme Cyclopentyl methyl ether CHCl ₃ Chloroform DCE 1,2-Dichloroethane DABCO 1,4-Diazabicyclo[2.2.2]octane DCM Dichloromethane DMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Dppf, DPPF or dppf 1,1'-Bis(diphenylphosphino)ferrocene eq or eq. or equiv. Equivalent ESI or ES Electrospray Ionization Et Ethyl _Et2O Ether EtOAc Ethyl acetate EtOH Ethanol g Grams h Hours H ₂ 0 water HPLC High Pressure Liquid Chromatography i Isopropyl IPA Isopropyl alcohol IPA Isopropyl acetate iPr ₂ NEt or DIPEA N-Ethyldiisopropylamine (Hünig's base) KHMDS Potassium bis(trimethylsilyl)amide KK Potassium acetate LDA Lithium diisopropylamide Lawesson's reagent 2,4-Bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiodiphosphacyclobutane, 2,4-Bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphacyclobutane 2,4-disulfide LC MS, LCMS, LC-MS or LC/MS Liquid chromatography-mass spectrometry LG Deoxylates (e.g. halogens, mesylates, triflates) LHMDS or LiHMDS Lithium bis(trimethylsilyl)amide m/z Mass-to-charge ratio Me methyl MeCN Acetonitrile MeOH Methanol Met Metal species used for cross-coupling (e.g., MgX, ZnX, SnR ₃ , SiR ₃ , B(OR) ₂ ) 2-MeTHF 2-Methyltetrahydrofuran mg mg min minute MIBK 4-Methyl-2-pentanone mL mL MS Mass Spectrometry MTBE Methyl tert-butyl ether n-BuLi n-Butyl lithium NaHMDS Sodium bis(trimethylsilyl)amide NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NMR Nuclear Magnetic Resonance Pd ₂ (dba) ₃ Dipalladium(II)(dibenzylideneacetone)(0) Pd(dppf)Cl ₂ ·DCM [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane Pd(PPh ₃ ) ₄ Tetrakis(triphenylphosphine)palladium(0) Ph Phenyl PR or PG or Prot. Group Protection Group rbf Round bottom flask RP-HPLC Reversed Phase High Pressure Liquid Chromatography RT or rt Room temperature sat. or satd. Saturated SFC Supercritical liquid phase separation SPhos Pd G3 or SPhos G3 Palladium(II) methanesulfonate (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)) TBAF Tetrabutylammonium fluoride TBTU N,N,N',N' -Tetramethyl- O- (benzotriazol-1-yl)uronium tetrafluoroborate t -BuOH Tertiary Butanol TEA or _Et3N Trimethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran UV XRPD UV X-ray powder diffraction

除非另外指示，否則在描述本發明的上下文中（尤其是在申請專利範圍的上下文中）術語「一個（種）（a或an）」及「該（the）」及類似參考物的使用應解釋為涵蓋單數及複數兩者。除非本文另外指示，否則本文有關值的範圍的陳述僅意欲用作個別地提及在該範圍內的每一獨立值的簡寫方法，且每一獨立值係併入說明書中，就如同在本文個別地陳述該值一般。除非另外要求，否則本文所提供的任何及所有實例，或示例性語言（例如「例如」）的使用旨在更好地說明本發明且並非對本發明範圍的限制。本說明書中的語言均不應解釋為指示任何非要求的要素為實踐本發明必不可少的。Unless otherwise indicated, the use of the terms "a or an" and "the" and similar references in the context of describing the present invention (especially in the context of claim scope) should be construed to cover both the singular and the plural. Unless otherwise indicated herein, the statement of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value within the range, and each separate value is incorporated into the specification as if it were individually stated herein. Unless otherwise required, any and all examples provided herein, or the use of exemplary language (e.g., "for example"), are intended to better illustrate the present invention and are not intended to be a limitation on the scope of the present invention. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

如本文所用，術語「烷基」係指直鏈及支鏈C₁ -C₈ 烴基，包括但不限於甲基、乙基、正-丙基、異-丙基、正-丁基、二級-丁基、三級-丁基、正-戊基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、正-己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基及2-乙基丁基。術語C_m-n 意指具有「m」至「n」個碳原子的烷基。術語「伸烷基」係指具有取代基的烷基。烷基（例如甲基）或伸烷基（例如-CH₂ -）基團可以經一個或多個，且通常一個至三個獨立地選自例如以下的基團取代：鹵基、三氟甲基、三氟甲氧基、羥基、烷氧基、硝基、氰基、烷基胺基、C_1-8 烷基、C_2-8 烯基、C_2-8 炔基、-NC、胺基、-CO₂ H、-CO₂ C₁ -C₈ 烷基、-OCOC₁ -C₈ 烷基、C₃ -C₁₀ 環烷基、C₃ -C₁₀ 雜環烷基、C₅ -C₁₀ 芳基及C₅ -C₁₀ 雜芳基。術語「鹵代烷基」特別地指烷基基團，其中該烷基基團的至少一個（例如，1至6個）或所有氫被鹵基原子取代。As used herein, the term "alkyl" refers to straight and branched _C1 - _C8 alkyl groups, including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, di-butyl, tertiary-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. The term _Cmn means an alkyl group having "m" to "n" carbon atoms. The term "alkylene" refers to an alkyl group having a substituent. The alkyl (e.g. methyl) or alkylene (e.g. -CH ₂ -) group may be substituted by one or more, and typically one to three, groups independently selected from, for example, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, -NC, amine, -CO ₂ H, -CO ₂ C ₁ -C ₈ alkyl, -OCOC ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, C ₅ -C ₁₀ aryl and C ₅ -C ₁₀ heteroaryl. The term "halogenated alkyl" refers specifically to an alkyl group in which at least one (e.g. 1 to 6) or all hydrogen atoms of the alkyl group are replaced by halogen atoms.

術語「烯基」及「炔基」分別指示進一步包括雙鍵或三鍵的烷基。The terms "alkenyl" and "alkynyl" refer to alkyl groups further including double or triple bonds, respectively.

如本文所用，術語「鹵基」係指氟、氯、溴及碘。術語「烷氧基」定義為-OR，其中R係烷基。As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "alkoxy" is defined as -OR, where R is an alkyl group.

如本文所用，術語「胺基」或「胺」可互換地指-NR₂ 基團，其中每個R係例如H或取代基。在一些實施方式中，胺基進一步被取代以形成銨離子，例如NR₃ ⁺ 。銨部分特別地包括於「胺基」或「胺」的定義中。取代基可以是例如烷基、烷氧基、環烷基、雜環烷基、醯胺或羧酸酯。R基團可以進一步例如經一個或多個（例如一個至四個）選自以下的基團取代：鹵基、氰基、烯基、炔基、烷基、環烷基、雜環烷基、芳基、雜芳基、脲、羰基、羧酸酯、胺及醯胺。「醯胺」或「醯胺基」基團可互換地指與胺或胺基基團類似但另外包括C(O)的基團，例如-C(O)NR₂ 。As used herein, the term "amino" or "amine" refers interchangeably to a _-NR2 group, wherein each R is, for example, H or a substituent. In some embodiments, the amino group is further substituted to form an ammonium ion, such as _NR3 ⁺ . The ammonium moiety is specifically included in the definition of "amino" or "amine". The substituent can be, for example, an alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amide, or carboxylate. The R group can be further substituted, for example, with one or more (e.g., one to four) groups selected from the following: halogen, cyano, alkenyl, alkynyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylate, amine, and amide. "Amid" or "amido" groups refer interchangeably to groups similar to amine or amido groups but that additionally include C(O), for example -C(O) _NR2 .

如本文所用，術語「芳基」係指C_6-14 單環或多環芳香族基團，較佳的是C_6-10 單環或二環芳香族基團、或C_10-14 多環芳香族基團。芳基的實例包括但不限於苯基、萘基、茀基、薁基、蒽基、菲基、芘基、聯苯基及三聯苯基。芳基亦指C_10-14 二環及三環碳環，其中一個環係芳香族的並且其他環係飽和的、部分不飽和的或芳香族的，例如二氫萘基、茚基、二氫茚基或四氫萘基（四氫化萘基）。除非另外指示，否則芳基基團可以未經取代或經一個或多個且特別是一個至四個獨立地選自例如以下的基團取代：鹵基、C₁ -₈ 烷基、C₂ -₈ 烯基、C₂ -₈ 炔基、-CF₃ 、-OCF₃ 、-NO₂ 、-CN、-NC、-OH、烷氧基、胺基、-CO₂ H、-CO₂ C₁ -C₈ 烷基、-OCOC₁ -C₈ 烷基、C₃ -C₁₀ 環烷基、C₃ -C₁₀ 雜環烷基、C₅ -C₁₀ 芳基及C₅ -C₁₀ 雜芳基。As used herein, the term "aryl" refers to a C _6-14 monocyclic or polycyclic aromatic group, preferably a C _6-10 monocyclic or bicyclic aromatic group, or a C _10-14 polycyclic aromatic group. Examples of aryl include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl and terphenyl. Aryl also refers to C _10-14 bicyclic and tricyclic carbon rings, one of which is aromatic and the other rings are saturated, partially unsaturated or aromatic, such as dihydronaphthyl, indenyl, dihydroindenyl or tetrahydronaphthyl (tetrahydronaphthyl). Unless otherwise indicated, an aryl group may be unsubstituted or substituted by one or more, and in particular one to four, groups independently selected, for example, from halogen, C ₁ _-8 alkyl, C ₂ -8 alkenyl, C _{2 -8} _alkynyl , _-CF ₃ , -OCF ₃ , -NO ₂ , -CN, -NC, -OH, alkoxy, amine, -CO ₂ H, -CO ₂ C ₁ -C ₈ alkyl, -OCOC ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, C ₅ -C ₁₀ aryl and C ₅ -C ₁₀ heteroaryl.

如本文所用，術語「環烷基」係指單環或多環非芳香族碳環，其中多環的環可以是稠合的、橋接的或螺環的。碳環可以具有3至10個碳環原子。考慮到的碳環包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環辛基及環壬基。As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic carbocyclic ring, wherein the polycyclic rings may be fused, bridged or spirocyclic. The carbocyclic ring may have 3 to 10 carbocyclic ring atoms. Contemplated carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.

如本文所用，術語「雜環烷基」意指單環或多環（例如，二環）、飽和的或部分不飽和的環系統，其含有3個或更多個（例如，3至12、4至10、4至8或5至7個）總原子，其中1-5個（例如，1、2、3、4或5個）原子獨立地選自氮、氧及硫。雜環烷基的非限制性實例包括氮雜環丁烷基、吡咯啶基、哌啶基、哌𠯤基、二氫吡咯基、嗎啉基、硫嗎啉基、二氫吡啶基、氧雜環庚基、二氧雜環庚基、硫雜環庚基及二氮雜環庚基。As used herein, the term "heterocycloalkyl" means a monocyclic or polycyclic (e.g., bicyclic), saturated or partially unsaturated ring system containing 3 or more (e.g., 3 to 12, 4 to 10, 4 to 8, or 5 to 7) total atoms, of which 1-5 (e.g., 1, 2, 3, 4, or 5) atoms are independently selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocycloalkyl include azacyclobutane, pyrrolidinyl, piperidinyl, piperonyl, dihydropyrrolyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxahedralheptyl, dioxahedralheptyl, thiadralheptyl, and diazacycloheptyl.

除非另外指示，否則環烷基或雜環烷基基團可以未經取代或經一個或多個且特別是一個至四個基團取代。一些考慮到的取代基包括鹵基、C₁ -₈ 烷基、C₂ -₈ 烯基、C₂ -₈ 炔基、-OCF₃ 、-NO₂ 、-CN、-NC、-OH、烷氧基、胺基、-CO₂ H、-CO₂ C₁ -C₈ 烷基、-OCOC₁ -C₈ 烷基、C₃ -C₁₀ 環烷基、C₃ -C₁₀ 雜環烷基、C₅ -C₁₀ 芳基及C₅ -C₁₀ 雜芳基。Unless otherwise indicated, a cycloalkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more, and in particular _{one to four, groups. Some contemplated substituents include halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8} _alkynyl _, _-OCF ₃ , _-NO ₂ , -CN, -NC, -OH, alkoxy, amine, _-CO ₂ H, -CO ₂ C ₁ -C ₈ alkyl, -OCOC ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, C ₅ -C ₁₀ aryl, and C ₅ -C ₁₀ heteroaryl.

如本文所用，術語「雜芳基」係指含有一個至三個芳香族環且在芳香族環中含有一個至四個（例如1、2、3或4個）選自氮、氧及硫的雜原子的單環或多環系統（例如雙環）。在某些實施方式中，雜芳基具有5至20、5至15、5至10個環，或5至7個原子。雜芳基亦指C_10-14 二環及三環的環，其中一個環係芳香族的並且其他環係飽和的、部分不飽和的或芳香族的。雜芳基的實例包括但不限於，呋喃基、咪唑基、異噻唑基、異噁唑基、噁二唑基、噁唑基、吡𠯤基、吡唑基、嗒𠯤基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三𠯤基、三唑基、苯并呋喃基、苯并咪唑基、苯并異噁唑基、苯并哌喃基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并苯硫基、苯并三唑基、苯并噁唑基、呋喃并吡啶基、咪唑并吡啶基、咪唑并噻唑基、吲口巾基、吲哚基、吲唑基、異苯并呋喃基、異苯并噻吩基、異吲哚基、異喹啉基、異噻唑基、口奈啶基、噁唑并吡啶基、酞𠯤基、喋啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹㗁啉基、喹唑啉基、噻二唑并嘧啶基及噻吩并吡啶基。除非另外指示，否則雜芳基基團可以未經取代或經一個或多個且特別是一個至四個或一個或兩個取代基取代。考慮到的取代基包括鹵基、C₁ -₈ 烷基、C₂ -₈ 烯基、C₂ -₈ 炔基、-OCF₃ 、-NO₂ 、-CN、-NC、-OH、烷氧基、胺基、-CO₂ H、-CO₂ C₁ -C₈ 烷基、-OCOC₁ -C₈ 烷基、C₃ -C₁₀ 環烷基、C₃ -C₁₀ 雜環烷基、C₅ -C₁₀ 芳基及C₅ -C₁₀ 雜芳基。As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic system (e.g., bicyclic) containing one to three aromatic rings and one to four (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the aromatic rings. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, 5 to 10 rings, or 5 to 7 atoms. Heteroaryl also refers to C _10-14 bicyclic and tricyclic rings, in which one ring is aromatic and the other rings are saturated, partially unsaturated, or aromatic. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazolyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzo The term "heteroaryl" refers to an aryl radical, which is substituted with one or more substituents, and is substituted with one or more substituents, and is preferably substituted with one or more substituents. The term "heteroaryl" refers to an aryl radical, which is substituted with one or more substituents, and is preferably ... Contemplated substituents include halogen, C ₁ _-8 alkyl, C ₂ _-8 alkenyl, C ₂ _-8 alkynyl, -OCF ₃ , -NO ₂ , -CN, -NC, -OH, alkoxy, amine, -CO ₂ H, -CO ₂ C ₁ -C ₈ alkyl, -OCOC ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, C ₅ -C ₁₀ aryl, and C ₅ -C ₁₀ heteroaryl.

如本文所用，術語Boc係指結構。實施方式 實施方式 1 As used herein, the term Boc refers to the structure . Implementation Method Implementation Method 1

在本發明的一個實施方式中，本發明包括一種組成物，該組成物包含具有式4之化合物及具有式B之化合物。實施方式 2 In one embodiment of the present invention, the present invention includes a composition comprising a compound having formula 4 and a compound having formula B . Implementation Method 2

在本發明的另一個實施方式中，本發明包括如實施方式1所述之組成物，其中具有式4之化合物為具有式5M之化合物：。實施方式 3 In another embodiment of the present invention, the present invention includes the composition as described in Embodiment 1, wherein the compound having Formula 4 is a compound having Formula 5M: . Implementation Method 3

在本發明的另一個實施方式中，本發明包括如實施方式1所述之組成物，其中具有式4之化合物為具有式5P之化合物：。實施方式 4 In another embodiment of the present invention, the present invention includes the composition as described in Embodiment 1, wherein the compound having Formula 4 is a compound having Formula 5P: Implementation Method 4

在本發明的另一個實施方式中，本發明包括如實施方式1-3中任一項所述之組成物，其中具有式B之化合物為具有式B1之化合物。實施方式 5 In another embodiment of the present invention, the present invention includes a composition as described in any one of embodiments 1-3, wherein the compound having formula B is a compound having formula B1 Implementation Method 5

在本發明的另一個實施方式中，本發明包括如實施方式1-3中任一項所述之組成物，其中具有式B之化合物為具有式B2之化合物。。實施方式 6 In another embodiment of the present invention, the present invention includes the composition as described in any one of Embodiments 1-3, wherein the compound having Formula B is a compound having Formula B2. Implementation Method 6

在本發明的另一個實施方式中，本發明包括如實施方式1-5中任一項所述之組成物，其中該組成物包含2:1比率的具有式4之化合物與具有式B之化合物。實施方式 7 In another embodiment of the present invention, the present invention includes a composition as described in any one of Embodiments 1-5, wherein the composition comprises a compound having Formula 4 and a compound having Formula B in a ratio of 2:1. Embodiment 7

在本發明的另一個實施方式中，本發明包括如實施方式1-6中任一項所述之組成物，其中該組成物進一步包含具有下式之2-甲基四氫呋喃。實施方式 8 In another embodiment of the present invention, the present invention includes a composition as described in any one of embodiments 1-6, wherein the composition further comprises 2-methyltetrahydrofuran having the formula . Implementation Method 8

在本發明的另一個實施方式中，本發明包括如實施方式1-7中任一項所述之組成物，其中2-甲基四氫呋喃與具有式B之化合物的比率為2:1。實施方式 9 In another embodiment of the present invention, the present invention comprises a composition as described in any one of Embodiments 1-7, wherein the ratio of 2-methyltetrahydrofuran to the compound having formula B is 2:1. Embodiment 9

在本發明的另一個實施方式中，本發明包括如實施方式1所述之組成物，其中該組成物具有下式。實施方式 10 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 1, wherein the composition has the following formula Implementation Method 10

在本發明的另一個實施方式中，本發明包括如實施方式9所述之組成物，其中該組成物具有下式。實施方式 11 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 9, wherein the composition has the following formula Implementation Method 11

在本發明的另一個實施方式中，本發明包括如實施方式9所述之組成物，其中該組成物具有下式。實施方式 12 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 9, wherein the composition has the following formula Implementation Method 12

在本發明的另一個實施方式中，本發明包括如實施方式9所述之組成物，其中該組成物具有下式。實施方式 13 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 9, wherein the composition has the following formula Implementation Method 13

在本發明的另一個實施方式中，本發明包括如實施方式9所述之組成物，其中該組成物具有下式。實施方式 14 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 9, wherein the composition has the following formula Implementation Method 14

在本發明的另一個實施方式中，本發明包括如實施方式1-13中任一項所述之組成物，其中該組成物處於結晶狀態。實施方式 15 In another embodiment of the present invention, the present invention includes a composition as described in any one of embodiments 1 to 13, wherein the composition is in a crystalline state .

在本發明的另一個實施方式中，本發明包括一種製備具有式4a之組成物之方法，該方法包括在2-甲基四氫呋喃存在下，使具有以下化學結構4的化合物4與具有下式之化合物B1 反應以形成具有以下結構的具有式4a之組成物：4a。實施方式 16 In another embodiment of the present invention, the present invention includes a method for preparing a composition having formula 4a, the method comprising reacting a compound having the following chemical structure in the presence of 2-methyltetrahydrofuran: Compound 4 of 4 and compound B1 having the following formula Reaction to form a composition of formula 4a having the following structure: 4a. Implementation 16

在本發明的另一個實施方式中，本發明包括獲得具有以下化學結構的具有式5M之化合物的方法，該方法包括： a) 在2-甲基四氫呋喃存在下，使具有以下化學結構的化合物4與具有下式之化合物B1 反應以形成晶體形式的具有以下結構的具有式4a之組成物：； b) 分離組成物4a， c) 用鹼處理該分離的組成物4a以產生該具有式5M之化合物。實施方式 17 In another embodiment of the present invention, the present invention includes obtaining a compound having the following chemical structure: The method comprises: a) in the presence of 2-methyltetrahydrofuran, Compound 4 and compound B1 having the following formula reacted to form a composition of formula 4a having the following structure in crystalline form: b) isolating composition 4a, c) treating the separated composition 4a with a base to produce the compound of formula 5M.

在本發明的另一個實施方式中，本發明包括如實施方式16所述之方法，其中鹼係Na₂ HPO₄ 。實施方式 18 In another embodiment of the present invention, the present invention includes the method as described in Embodiment 16, wherein the base is Na ₂ HPO ₄ . Embodiment 18

在本發明的另一個實施方式中，本發明包括如實施方式16所述之方法，其中鹼係NaHCO₃ 。實施方式 19 In another embodiment of the present invention, the present invention includes the method as described in Embodiment 16, wherein the base is NaHCO ₃ . Embodiment 19

在本發明的另一個實施方式中，本發明包括組成物，該組成物包含具有式4之化合物及具有式11之化合物。實施方式 20 In another embodiment of the present invention, the present invention includes a composition comprising a compound having formula 4 And a compound having formula 11 Implementation Method 20

在本發明的另一個實施方式中，本發明包括如實施方式19所述之組成物，其中具有式4之化合物為具有式5M之化合物：。實施方式 21 In another embodiment of the present invention, the present invention includes the composition as described in Embodiment 19, wherein the compound having Formula 4 is a compound having Formula 5M: Implementation Method 21

在本發明的另一個實施方式中，本發明包括如實施方式19所述之組成物，其中具有式4之化合物為具有式5P之化合物：。實施方式 22 In another embodiment of the present invention, the present invention includes the composition as described in Embodiment 19, wherein the compound having Formula 4 is a compound having Formula 5P: Implementation Method 22

在本發明的另一個實施方式中，本發明包括如實施方式19-21中任一項所述之組成物，其中具有式11之化合物為具有式11a之化合物。實施方式 23 In another embodiment of the present invention, the present invention includes a composition as described in any one of Embodiments 19-21, wherein the compound having Formula 11 is a compound having Formula 11a Implementation Method 23

在本發明的另一個實施方式中，本發明包括如實施方式19-21中任一項所述之組成物，其中具有式11之化合物為具有式11b之化合物。。實施方式 24 In another embodiment of the present invention, the present invention includes the composition as described in any one of Embodiments 19-21, wherein the compound having Formula 11 is a compound having Formula 11b. Implementation Method 24

在本發明的另一個實施方式中，本發明包括如實施方式19所述之組成物，其中該組成物具有下式：。實施方式 25 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 19, wherein the composition has the following formula: Implementation Method 25

在本發明的另一個實施方式中，本發明包括如實施方式19所述之組成物，其中該組成物具有下式：。實施方式 26 In another embodiment of the present invention, the present invention includes a composition as described in embodiment 19, wherein the composition has the following formula: Implementation Method 26

在本發明的另一個實施方式中，本發明包括如實施方式19所述之組成物，其中該組成物具有下式：。實施方式 27 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 19, wherein the composition has the following formula: Implementation Method 27

在本發明的另一個實施方式中，本發明包括如實施方式19所述之組成物，其中該組成物具有下式：。實施方式 28 In another embodiment of the present invention, the present invention includes a composition as described in Embodiment 19, wherein the composition has the following formula: Implementation Method 28

在本發明的另一個實施方式中，本發明包括如實施方式19-27中任一項所述之組成物，其中該組成物包含1：1比率的具有式4之化合物與具有式11之化合物。實施方式 29 In another embodiment of the present invention, the present invention includes a composition as described in any one of Embodiments 19-27, wherein the composition comprises a compound having Formula 4 and a compound having Formula 11 in a 1:1 ratio. Embodiment 29

在本發明的另一個實施方式中，本發明包括如實施方式16所述之方法，其中具有式5M之化合物用於產生具有下式之化合物。本揭露的化合物 In another embodiment of the present invention, the present invention includes the method as described in Embodiment 16, wherein the compound of formula 5M is used to produce a compound of formula The compounds disclosed herein

本文提供了具有下面更詳細討論的結構的KRAS抑制劑。Provided herein are KRAS inhibitors having structures discussed in more detail below.

本文所揭露的化合物包括所有藥學上可接受的同位素標記的化合物，其中本文所揭露的化合物的一個或多個原子由具有相同原子序數、但原子質量或質量數與通常在自然界中發現的原子質量或質量數不同的原子替代。可以摻入所揭露化合物中的同位素的實例包括氫、碳、氮、氧、磷、氟、氯及碘的同位素，分別是例如² H、³ H、¹¹ C、¹³ C、¹⁴ C、¹³ N、¹⁵ N、¹⁵ O、¹⁷ O、¹⁸ O、³¹ P、³² P、³⁵ S、¹⁸ F、³⁶ Cl、¹²³ I及¹²⁵ I。該等放射性標記的化合物可用於説明藉由表徵例如作用位點或方式，或與藥理學上重要的作用位點的結合親和性，來確定或量測化合物的有效性。本揭露的某些同位素標記的化合物（例如，那些摻入放射性同位素的化合物）可用於藥物及/或受質組織分佈研究中。鑒於易於摻入以及即用的偵測方式，放射性同位素氚（即³ H）及碳-14（即¹⁴ C）尤其可用於這個目的。The compounds disclosed herein include all pharmaceutically acceptable isotopically labeled compounds, wherein one or more atoms of the compounds disclosed herein are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, 13 C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. Such radiolabeled compounds can be used to help determine or measure the effectiveness of the compounds by characterizing ^, for example, the site or mode of action, or the binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of the present disclosure (e.g., those incorporating a radioactive isotope) are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose due to their ease of incorporation and ready-to-use detection methods.

用較重同位素（例如氘，即² H）取代可以提供源自較高代謝穩定性的某些治療優勢（例如，延長的體內半衰期或降低的劑量要求），並且因此在一些情況下是較佳的。Substitution with heavier isotopes (such as deuterium ( ^2H )) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

用正電子發射同位素（例如¹¹ C、¹⁸ F、¹⁵ O及¹³ N）取代可用於正電子發射斷層掃描（PET）研究，以檢查受質受體佔有率。結構 (I) 的同位素標記的化合物通常可以藉由熟習此項技術者已知的習知技術，或者藉由與如下文所述的製備及實例（Preparations and Examples）中所述的那些類似的方法，使用適當的同位素標記的試劑代替先前採用的未經標記的試劑來製備。Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be used in positron emission tomography (PET) studies to examine receptor occupancy. Isotopically labeled compounds of structure (I) can generally be prepared by techniques known to those skilled in the art, or by methods analogous to those described in the Preparations and Examples, as described below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

如本文所揭露的同位素標記的化合物通常可以藉由熟習此項技術者已知的習知技術，或者藉由與所附實例及方案中所述的那些類似的方法，使用適當的同位素標記的試劑代替先前採用的未經標記的試劑來製備。Isotopically labeled compounds as disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by procedures analogous to those described in the accompanying Examples and Schemes, using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.

如本文所揭露的某些化合物可以作為立體異構物（即，只有原子的空間排布不同的異構物）存在，包括光學異構物及構象異構物（或構象物）。本文所揭露的化合物包括作為純的個別立體異構物製劑及每一種的富集製劑的所有立體異構物、以及此類立體異構物的外消旋混合物以及可以根據熟習此項技術者已知的方法分離的個別非鏡像異構物及鏡像異構物。另外，本文所揭露的化合物包括該等化合物的所有互變異構物形式。Certain compounds as disclosed herein may exist as stereoisomers (i.e., isomers that differ only in the spatial arrangement of atoms), including optical isomers and conformational isomers (or conformers). The compounds disclosed herein include all stereoisomers as pure individual stereoisomer preparations and enriched preparations of each, as well as racemic mixtures of such stereoisomers and individual non-mirror image isomers and mirror image isomers that can be separated according to methods known to those skilled in the art. In addition, the compounds disclosed herein include all tautomeric isomer forms of the compounds.

某些本文所揭露的化合物可以作為阻轉異構物存在，其為在由於與分子其他部分的空間相互作用，圍繞分子中單鍵的旋轉被阻止或大大減慢時出現的構象立體異構物。本文所揭露的化合物包括作為純的個別阻轉異構物製劑、每一種的富集製劑或者每一種的非特定混合物的所有阻轉異構物。若圍繞單鍵的旋轉勢壘足夠高，並且構象之間的互變足夠緩慢，則可以容許異構物種類的分離及分開。例如，基團例如但不限於以下基團、、及可能展現受限的旋轉。Certain compounds disclosed herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with the rest of the molecule. The compounds disclosed herein include all atropisomers as pure preparations of individual atropisomers, enriched preparations of each, or non-specific mixtures of each. If the rotation potential about the single bond is high enough and the interconversion between conformations is slow enough, then separation and isolation of the isomeric species may be permitted. For example, groups such as, but not limited to, the following groups , , and May exhibit limited rotation.

術語「一水合物」係指具有約一個締合的水分子的化合物9的鹽。熟習此項技術者將理解，締合的水分子的確切數目可以在任何時間隨可變的溫度、壓力及其他環境影響略有變化。締合的水分子的數目的所有細微變化均預期在本發明的範圍內。The term "monohydrate" refers to a salt of compound 9 that has about one associated water molecule. Those skilled in the art will appreciate that the exact number of associated water molecules may vary slightly at any time due to variable temperature, pressure, and other environmental influences. All slight variations in the number of associated water molecules are contemplated within the scope of the present invention.

術語「二水合物」係指具有約兩個締合的水分子的化合物9的鹽。熟習此項技術者將理解，締合的水分子的確切數目可以在任何時間隨可變的溫度、壓力及其他環境影響略有變化。締合的水分子的數目的所有細微變化均預期在本發明的範圍內。The term "dihydrate" refers to a salt of compound 9 that has about two associated water molecules. Those skilled in the art will appreciate that the exact number of associated water molecules may vary slightly at any time due to variable temperature, pressure, and other environmental influences. All slight variations in the number of associated water molecules are contemplated within the scope of the present invention.

術語「共晶體」係指在環境溫度（20℃至25℃，較佳的是20℃）下包含兩種或更多種化合物的結晶材料，其中至少兩種藉由弱相互作用結合在一起，其中化合物中的至少一種係共晶體形成劑，並且另一種係化合物5。弱相互作用定義為既不是離子鍵亦非共價鍵的相互作用，並且例如包括：氫鍵、凡得瓦力及π-π相互作用。The term "eutectic" refers to a crystalline material comprising two or more compounds at ambient temperature (20°C to 25°C, preferably 20°C), at least two of which are bound together by weak interactions, wherein at least one of the compounds is a eutectic former and the other is compound 5. Weak interactions are defined as interactions that are neither ionic nor covalent, and include, for example, hydrogen bonds, van der Waals forces, and π-π interactions.

術語「非晶形形式」或「非晶形」係指缺乏長程有序並且因此未顯示出明顯的X射線衍射峰（即布拉格衍射峰）的材料。非晶形材料的XRPD圖的特徵在於一個或多個非晶形暈。The term "amorphous form" or "amorphous" refers to a material that lacks long-range order and therefore does not display distinct X-ray diffraction peaks (ie, Bragg diffraction peaks). An XRPD pattern of an amorphous material is characterized by one or more amorphous halos.

術語「非晶形暈」係非晶形物質的X射線粉末圖中的近似鐘形的最大值。The term "amorphous halo" refers to the approximately bell-shaped maximum in the X-ray powder pattern of an amorphous material.

術語「基本上純的」係指化合物9的固體形式，其純度大於約95%，具體地大於約99.5%，更具體地大於約99.8%，並且仍更具體地大於約99.9%。The term "substantially pure" refers to a solid form of Compound 9 having a purity greater than about 95%, specifically greater than about 99.5%, more specifically greater than about 99.8%, and still more specifically greater than about 99.9%.

術語「患者」係指動物，例如犬、貓、牛、馬、綿羊及人。特定患者係哺乳動物。術語患者包括雄性及雌性。The term "patient" refers to animals, such as dogs, cats, cattle, horses, sheep, and humans. Particular patients are mammals. The term patient includes males and females.

術語「治療（treating、treat或treatment）」及其類似物包括預防性（preventative）（例如預防性（prophylactic））及緩解性治療。The terms "treating", "treat" or "treatment" and their congeners include preventative (eg, prophylactic) and palliative treatment.

術語「賦形劑」意指除活性藥物成分（API）以外任何藥學上可接受的添加劑、載劑、稀釋劑、佐劑或其他成分，其通常納入用於配製及/或投與患者。藥物組成物、給藥及投與途徑 The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient other than the active pharmaceutical ingredient (API) that is normally incorporated for formulation and/or administration to a patient. Drug Compositions, Administration and Routes of Administration

本文亦提供了藥物組成物，該等藥物組成物包含如本文所揭露的化合物以及藥學上可接受的賦形劑，例如稀釋劑或載劑。適合用於本發明的化合物及藥物組成物包括能以有效量投與化合物以實現其既定目的的那些。化合物的投與更詳細地描述於下文中。Also provided herein are pharmaceutical compositions comprising a compound as disclosed herein and a pharmaceutically acceptable excipient, such as a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those that can be administered in an effective amount to achieve their intended purpose. Administration of the compounds is described in more detail below.

適合的藥物配製物可以由技術人員根據投與途徑及所需劑量來決定。參見例如 ，Remington’s Pharmaceutical Sciences [雷明頓藥物科學], 1435-712（第18版，賓夕法尼亞州伊斯頓市馬克出版公司（Mack Publishing Co, Easton, Pennsylvania），1990）。配製物可以影響所投與藥劑的物理狀態、穩定性、體內釋放速率及體內清除速率。取決於投與途徑，可以根據體重、體表面積或器官尺寸來計算適合的劑量。熟習此項技術者在不進行過度實驗的情況下，尤其根據本文所揭露的劑量資訊及測定以及可藉由動物或人類臨床試驗獲得的藥物動力學資料，以習知方式進行決定適當治療劑量所需計算的進一步細化。The appropriate drug formulation can be determined by a skilled artisan based on the route of administration and the desired dosage. See, e.g. , Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). The formulation can affect the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered dose. Depending on the route of administration, the appropriate dosage can be calculated based on body weight, body surface area, or organ size. Further refinement of the calculations required to determine the appropriate therapeutic dose can be performed by one skilled in the art in an informed manner without undue experimentation, particularly based on the dosage information and assays disclosed herein and the pharmacokinetic data available from animal or human clinical trials.

短語「藥學上可接受的」或「藥理學上可接受的」係指在投與於動物或人類時不產生不良反應、過敏反應或其他不利反應的分子實體及組成物。如本文所用，「藥學上可接受的」包括任何及所有溶劑、分散介質、包衣、抗細菌劑及抗真菌劑、等滲劑及吸收延遲劑等。此類賦形劑用於藥學活性物質的使用係本領域所熟知的。除非任何習知介質或藥劑與治療組成物不相容，否則考慮將其用於治療組成物中。亦可以將補充性活性成分摻入組成物中。在示例性實施方式中，配製物可以包含玉米糖漿固體、高油酸紅花油、椰子油、大豆油、L-白胺酸、磷酸三鈣、L-酪胺酸、L-脯胺酸、乙酸L-離胺酸、DATEM（乳化劑）、L-麩醯胺酸、L-纈胺酸、磷酸氫二鉀、L-異白胺酸、L-精胺酸、L-丙胺酸、甘胺酸、L-天冬醯胺一水合物、L-絲胺酸、檸檬酸鉀、L-蘇胺酸、檸檬酸鈉、氯化鎂、L-組胺酸、L-甲硫胺酸、抗壞血酸、碳酸鈣、L-麩胺酸、L-胱胺酸二鹽酸鹽、L-色胺酸、L-天冬胺酸、氯化膽鹼、牛磺酸、m-肌醇、硫酸亞鐵、抗壞血酸棕櫚酸酯、硫酸鋅、L-肉鹼、α-生育酚乙酸酯、氯化鈉、煙醯胺、混合生育酚、泛酸鈣、硫酸酮、氯化硫胺素鹽酸鹽、維生素A棕櫚酸酯、硫酸錳、核黃素、鹽酸吡哆辛、葉酸、β-胡蘿蔔素、碘化鉀、葉綠醌、生物素、硒酸鈉、氯化鉻、鉬酸鈉、維生素D3及氰鈷胺。The phrase "pharmaceutically acceptable" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse reactions, allergic reactions or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. The use of such excipients for pharmaceutically active substances is well known in the art. Unless any known medium or agent is incompatible with the therapeutic composition, it is considered for use in the therapeutic composition. Supplementary active ingredients may also be incorporated into the composition. In an exemplary embodiment, the formulation may include corn syrup solids, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (emulsifier), L-glutamine, L-valamine, dipotassium hydrogen phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid , calcium carbonate, L-glutamine, L-cystine dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha-tocopheryl acetate, sodium chloride, niacinamide, mixed tocopherols, calcium pantothenate, ketone sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3 and cyanocobalamin.

化合物可以作為藥學上可接受的鹽存在於藥物組成物中。如本文所用，「藥學上可接受的鹽」包括例如鹼加成鹽及酸加成鹽。The compound may be present in the pharmaceutical composition as a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" includes, for example, base addition salts and acid addition salts.

藥學上可接受的鹼加成鹽可以用金屬或胺（例如鹼金屬及鹼土金屬或有機胺）來形成。化合物的藥學上可接受的鹽亦可以用藥學上可接受的陽離子來製備。適合的藥學上可接受的陽離子係熟習此項技術者所熟知的並且包括鹼金屬陽離子、鹼土金屬陽離子、銨陽離子及四級銨陽離子。碳酸鹽或碳酸氫鹽亦為可能的。用作陽離子的金屬的實例係鈉、鉀、鎂、銨、鈣或三價鐵等。適合的胺的實例包括異丙胺、三甲胺、組胺酸、N,N’-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、二環己胺、乙二胺、N-甲基葡糖胺及普魯卡因。Pharmaceutically acceptable alkali addition salts can be formed with metals or amines (e.g., alkali metals and alkali earth metals or organic amines). Pharmaceutically acceptable salts of compounds can also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal cations, alkali earth metal cations, ammonium cations, and quaternary ammonium cations. Carbonates or bicarbonates are also possible. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium, or trivalent iron, etc. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine.

藥學上可接受的酸加成鹽包括無機酸鹽或有機酸鹽。適合的酸鹽的實例包括鹽酸鹽、甲酸鹽、乙酸鹽、檸檬酸鹽、水楊酸鹽、硝酸鹽、磷酸鹽。其他適合的藥學上可接受的鹽係熟習此項技術者所熟知的並且包括例如甲酸、乙酸、檸檬酸、草酸、酒石酸或扁桃酸、鹽酸、氫溴酸、硫酸或磷酸；與有機羧酸、磺酸、磺酸基酸或磷酸基酸或N-取代的胺基磺酸，例如乙酸、三氟乙酸（TFA）、丙酸、乙醇酸、琥珀酸、馬來酸、羥基馬來酸、甲基馬來酸、富馬酸、蘋果酸、酒石酸、乳酸、草酸、葡糖酸、葡糖二酸、葡糖醛酸、檸檬酸、苯甲酸、肉桂酸、扁桃酸、水楊酸、4-胺基水楊酸、2-苯氧基苯甲酸、2-乙醯氧基苯甲酸、撲酸、菸酸或異菸酸的鹽；以及與胺基酸，例如在自然界中參與蛋白質合成的20種α胺基酸，例如麩胺酸或天冬胺酸，以及與苯乙酸、甲磺酸、乙磺酸、2-羥基乙磺酸、乙烷1,2-二磺酸、苯磺酸、4-甲基苯磺酸、萘2-磺酸、萘1,5-二磺酸、2-磷酸甘油酸或3-磷酸甘油酸、葡萄糖6-磷酸、N-環己基胺基磺酸（用於環己胺磺酸鹽的形成），或與其他酸性有機化合物，例如抗壞血酸的鹽。Pharmaceutically acceptable acid addition salts include inorganic acid salts or organic acid salts. Examples of suitable acid salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates, and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, formic, acetic, citric, oxalic, tartaric or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric or phosphoric acid; and organic carboxylic, sulfonic, sulfonic or phosphoric acid or N-substituted aminosulfonic acids, such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, apple acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucuronic acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2- Salts of phenoxybenzoic acid, 2-acetyloxybenzoic acid, pyruvic acid, niacin or isonicotinic acid; and salts with amino acids, such as the 20 alpha amino acids that are naturally involved in protein synthesis, such as glutamine or aspartic acid, and with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid, 2-phosphoglyceric acid or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylaminosulfonic acid (for the formation of cyclohexylaminosulfonic acid salts), or with other acidic organic compounds, such as ascorbic acid.

含有本文所揭露的化合物的藥物組成物能以習知方式來製造，例如藉由習知混合、溶解、造粒、糖衣丸製備、磨細、乳化、囊封、捕集或凍乾方法。適當的配製物取決於所選的投與途徑。Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a known manner, for example, by known mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Proper formulation depends on the chosen route of administration.

對於口服投與，可以藉由將本文所揭露的化合物與本領域熟知的藥學上可接受的賦形劑（例如載劑）組合來容易地配製適合的組成物。此類賦形劑及載劑使得能將本發明化合物配製為片劑、丸劑、糖衣丸、膠囊、液體、凝膠、糖漿、漿液、懸浮液等，以供要治療的患者口服攝食。用於口服使用的藥物製劑可以藉由以下方式來獲得：向如本文所揭露的化合物添加固體賦形劑，視需要研磨所得混合物，並且在添加適合的輔助劑後（若需要）加工顆粒混合物，獲得片劑或糖衣丸核心。適合的賦形劑包括例如填充劑及纖維素製劑。若需要，可以添加崩解劑。用於各種類型的配製物的藥學上可接受的成分係熟知的，並且可以是例如用於各種配製物類型的粘合劑（例如，天然或合成聚合物）、潤滑劑、界面活性劑、甜味及矯味劑、包衣材料、防腐劑、染料、增稠劑、佐劑、抗微生物劑、抗氧化劑及載劑。For oral administration, suitable compositions can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients (e.g., carriers) well known in the art. Such excipients and carriers enable the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding a solid excipient to a compound as disclosed herein, grinding the resulting mixture as necessary, and processing the granule mixture after adding suitable adjuvants (if necessary) to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added. Pharmaceutically acceptable ingredients for various types of formulations are well known and may be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavor enhancers, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants and carriers for various formulation types.

在口服投與治療有效量的本文所揭露的化合物時，組成物通常呈固體（例如，片劑、膠囊、丸劑、粉末或糖錠）或液體配製物（例如，水性懸浮液、溶液、酏劑或糖漿）的形式。When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition is generally in the form of a solid (e.g., tablet, capsule, pill, powder or lozenge) or a liquid formulation (e.g., aqueous suspension, solution, elixir or syrup).

在以片劑形式投與時，組成物可以另外含有功能性固體及/或固體載劑，例如明膠或佐劑。片劑、膠囊及粉末可以含有約1%至約95%化合物，並且較佳的是約15%至約90%化合物。When administered in tablet form, the composition may additionally contain functional solids and/or solid carriers, such as gelatin or adjuvants. Tablets, capsules and powders may contain about 1% to about 95% of the compound, and preferably about 15% to about 90% of the compound.

在以液體或懸浮液形式投與時，可以添加功能性液體及/或液體載劑，例如水、石油或動物或植物來源的油。組成物的液體形式可以進一步含有生理鹽水溶液、糖醇溶液、右旋糖或其他糖溶液或二醇。在以液體或懸浮液形式投與時，組成物可以含有以重量計約0.5%至約90%的本文所揭露的化合物，並且較佳的是約1%至約50%的本文所揭露的化合物。在考慮到的一個實施方式中，液體載劑係非水性的或基本上非水性的。對於以液體形式投與，組成物可以作為快速溶解的固體配製物來供應，用於在即將投與前溶解或懸浮。When administered in liquid or suspension form, functional liquids and/or liquid carriers may be added, such as water, petroleum, or oils of animal or plant origin. The liquid form of the composition may further contain physiological saline solution, sugar alcohol solution, dextrose or other sugar solution or glycol. When administered in liquid or suspension form, the composition may contain about 0.5% to about 90% by weight of the compound disclosed herein, and preferably about 1% to about 50% by weight of the compound disclosed herein. In one embodiment contemplated, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

在藉由靜脈內、經皮膚或皮下注射投與治療有效量的本文所揭露的化合物時，組成物呈無熱原、非經腸可接受的水溶液的形式。此類非經腸可接受的溶液的製備應充分考慮pH、等滲性、穩定性等，係在本領域技術範圍的。除了本文所揭露的化合物以外，用於靜脈內、經皮膚或皮下注射的較佳的組成物通常含有等滲媒劑。此類組成物可以經製備用於作為與界面活性劑（例如羥丙基纖維素）適當混合的游離鹼或藥理學上可接受的鹽於水中的溶液來投與。亦可以在甘油、液體聚乙二醇及其混合物中以及在油中製備分散液。在普通的儲存及使用條件下，該等製劑可以視需要含有防腐劑以防止微生物生長。When a therapeutically effective amount of the compound disclosed herein is administered by intravenous, transdermal or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions should fully consider pH, isotonicity, stability, etc., which is within the technical scope of this field. In addition to the compounds disclosed herein, the preferred compositions for intravenous, transdermal or subcutaneous injection usually contain isotonic media. Such compositions can be prepared for administration as a solution of a free base or a pharmacologically acceptable salt in water appropriately mixed with a surfactant (e.g., hydroxypropylcellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations may, if necessary, contain a preservative to prevent the growth of microorganisms.

可注射組成物可以包括無菌水性溶液、懸浮液或分散液，以及用於臨時製備無菌可注射溶液、懸浮液或分散液的無菌粉末。在所有實施方式中，該形式必須是無菌的，並且流動性必須達到存在易可注射性的程度。其必須在製造及儲存條件下穩定，並且必須藉由視需要包括防腐劑來抵抗微生物（例如細菌及真菌）的污染作用。載劑可以是溶劑或分散介質，其含有例如水、乙醇、多元醇（例如，甘油、丙二醇及液體聚乙二醇等）、其適合的混合物以及植物油。在考慮到的一個實施方式中，載劑係非水性的或基本上非水性的。適當流動性可以例如藉由以下方式來保持：藉由使用包衣，例如卵磷脂；在分散液的實施方式中藉由保持化合物的所需粒徑；以及藉由使用界面活性劑。對微生物作用的防止可以藉由各種抗細菌劑及抗真菌劑來實現，例如對羥苯甲酸酯、氯丁醇、酚、山梨酸、硫柳汞等。在許多實施方式中，包括等滲劑（例如，糖或氯化鈉）將是較佳的。可注射組成物的延長吸收可以藉由在組成物中使用吸收延遲劑（例如，單硬脂酸鋁及明膠）來實現。Injectable compositions can include sterile aqueous solutions, suspensions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions or dispersions. In all embodiments, the form must be sterile, and the fluidity must be such that there is easy injectability. It must be stable under manufacturing and storage conditions, and must resist the contamination of microorganisms (e.g., bacteria and fungi) by optionally including preservatives. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), a suitable mixture thereof, and a vegetable oil. In one embodiment contemplated, the carrier is non-aqueous or substantially non-aqueous. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin; by maintaining the desired particle size of the compound in the case of dispersions; and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many embodiments, it will be preferred to include isotonic agents (for example, sugars or sodium chloride). Prolonged absorption of injectable compositions can be achieved by using in the composition an absorption delaying agent (for example, aluminum monostearate and gelatin).

無菌可注射溶液藉由以下方式來製備：將活性化合物以所需量摻入視需要含有上文所列舉的各種其他成分的適當溶劑中，隨後過濾滅菌。通常，分散液藉由以下方式來製備：將各種經滅菌活性成分摻入無菌媒劑中，該媒劑含有基礎分散介質及來自上文所列舉的那些的其他所需成分。在用於製備無菌可注射溶液的無菌粉末的實施方式中，較佳的製備方法係真空乾燥及冷凍乾燥技術，其產生活性成分加來自其預先經無菌過濾的溶液的任何所需的其他成分的粉末。Sterile injectable solutions are prepared by mixing the active compound in the desired amount in an appropriate solvent containing, as required, various other ingredients listed above, followed by filtration and sterilization. Typically, dispersions are prepared by mixing various sterilized active ingredients in a sterile vehicle containing a basic dispersion medium and other required ingredients from those listed above. In the embodiment of sterile powders for preparing sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any other required ingredients from a previously sterile filtered solution thereof.

亦可以製備緩慢釋放或持續釋放配製物，以實現在胃腸道中與體液接觸的活性化合物的受控釋放，並且在血漿中提供基本上恒定且有效的活性化合物水平。例如，可以藉由溶解、擴散及離子交換中的一種或多種來控制釋放。另外，緩慢釋放方法可以藉由胃腸道內的可飽和或限制通路促進吸收。例如，出於這個目的，可以將化合物包埋於生物可降解聚合物、水溶性聚合物或二者的混合物以及視需要適合的界面活性劑的聚合物基質中。在這種情況下，包埋可以意指在聚合物基質中摻入微粒。亦藉由經由已知的分散液或乳液包衣技術囊封經分散的微粒或經乳化的微滴來獲得受控釋放配製物。Slow release or sustained release formulations can also be prepared to achieve controlled release of active compounds in contact with body fluids in the gastrointestinal tract, and to provide substantially constant and effective levels of active compounds in plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. In addition, slow release methods can promote absorption by saturable or restricted pathways in the gastrointestinal tract. For example, for this purpose, the compound can be embedded in a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of the two and an optionally suitable surfactant. In this case, embedding can mean the inclusion of microparticles in a polymer matrix. Controlled release formulations are also obtained by encapsulating dispersed microparticles or emulsified droplets via known dispersion or emulsion coating techniques.

對於藉由吸入投與，本發明的化合物便捷地以氣溶膠噴霧劑呈遞的形式從加壓包裝或霧化器使用適合的推進劑來遞送。在加壓氣溶膠的實施方式中，可以藉由提供閥來確定劑量單位，以遞送經計量的量。用於吸入器或吹入器的例如明膠的膠囊及藥筒可以經配製含有化合物與適合的粉末基質（例如乳糖或澱粉）的粉末混合物。For administration by inhalation, the compounds of the invention are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant. In the embodiment of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

本文所揭露的化合物可以經配製用於藉由注射（例如，藉由推注或連續輸注）非經腸投與。注射用配製物能以單位劑型（例如，於安瓿中或於多劑量容器中）呈現，並添加有防腐劑。組成物可以採取例如以下等形式：於油性或水性媒劑中的懸浮液、溶液或乳液，並且可以含有配製劑，例如懸浮劑、穩定劑及/或分散劑。The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Injectable formulations can be presented in unit dosage form (e.g., in ampoules or in multi-dose containers) with added preservatives. The compositions can take the form of, for example, suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulators, such as suspending agents, stabilizers and/or dispersants.

用於非經腸投與的藥物配製物包括呈水溶性形式的化合物的水溶液。另外，可以將化合物的懸浮液製備為適當的油性注射懸浮液。適合的親脂性溶劑或媒劑包括脂肪油或合成脂肪酸酯。水性注射懸浮液可以含有提高懸浮液粘度的物質。視需要，懸浮液亦可以含有適合的穩定劑或提高化合物的溶解度並允許製備高度濃縮的溶液的試劑。可替代地，本發明組成物可以呈粉末形式以供在使用前用適合的媒劑（例如，無菌無熱原水）構造。Pharmaceutical formulations for parenteral administration include aqueous solutions of compounds in water-soluble form. In addition, suspensions of the compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. If necessary, the suspension can also contain suitable stabilizers or reagents that increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the composition of the present invention can be in powder form for construction with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

本文所揭露的化合物亦可以配製於直腸組成物中，例如栓劑或滯留型灌腸劑（例如，含有習知栓劑基質）。除了先前所述的配製物以外，亦可以將化合物配製為長效製劑。此類長效配製物可以藉由植入（例如，皮下或肌內）或藉由肌內注射來投與。因此，例如，化合物可以用適合的聚合或疏水材料（例如，作為可接受的油中的乳液）或離子交換樹脂，或作為微溶衍生物（例如，作為微溶鹽）來配製。The compounds disclosed herein can also be formulated in rectal compositions, such as suppositories or retention enemas (e.g., containing known suppository bases). In addition to the formulations previously described, the compounds can also be formulated as long-acting preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative (e.g., as a sparingly soluble salt).

特別地，本文所揭露的化合物能以含有賦形劑（例如澱粉或乳糖）的片劑的形式，或以單獨的或與賦形劑混合的膠囊或珠囊（ovule），或以含有矯味劑或著色劑的酏劑或懸浮液的形式，口服、經頰或舌下投與。此類液體製劑可以用藥學上可接受的添加劑（例如懸浮劑）來製備。亦可以非經腸注射化合物，例如靜脈內、肌內、皮下或冠狀動脈內。對於非經腸投與，化合物最佳地以無菌水溶液的形式來使用，其可以含有其他物質，例如鹽或糖醇（例如甘露醇）或葡萄糖，以使溶液與血液等滲。In particular, the compounds disclosed herein can be administered orally, buccally or sublingually in the form of tablets containing excipients (e.g., starch or lactose), or in capsules or ovules alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring agents or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives (e.g., suspensions). The compounds can also be injected parenterally, e.g., intravenously, intramuscularly, subcutaneously or intracoronarily. For parenteral administration, the compounds are best used in the form of sterile aqueous solutions, which may contain other substances, such as salts or sugar alcohols (e.g., mannitol) or glucose, to make the solution isotonic with blood.

對於獸用，本文所揭露的化合物根據正規獸醫實踐作為適合地可接受的配製物來投與。獸醫可以容易地確定對於特定動物最適合的給藥方案及投與途徑。For veterinary use, the compounds disclosed herein are administered as a suitably acceptable formulation according to normal veterinary practice. A veterinarian can readily determine the most suitable dosing regimen and route of administration for a particular animal.

在一些實施方式中，可以將用於使用如本文所揭露的化合物（單獨的或與傳統地用於治療這種疾病的另一種藥劑或干預組合的）治療KRAS相關障礙的所有所需組分包裝至套組（kit）中。具體地，本發明提供了用於疾病的治療干預的套組，該套組包含經包裝的成套藥物，包括本文所揭露的化合物以及用於製備該藥物的可遞送形式的緩衝劑及其他組分；及/或用於遞送此類藥物的裝置；及/或用於與本文所揭露的化合物的組合療法的任何藥劑；及/或與藥物一起包裝的疾病治療說明書。說明書可以固定於任何可觸摸介質中，例如印刷紙張、或電腦可讀取的磁性或光學介質、或參考遠端電腦資料來源的說明，例如可藉由互聯網訪問的萬維網網頁。In some embodiments, all the components required for treating KRAS-related disorders using the compounds disclosed herein (alone or in combination with another agent or intervention traditionally used to treat such diseases) can be packaged into a kit. Specifically, the present invention provides a kit for therapeutic intervention of a disease, the kit comprising a packaged set of drugs, including the compounds disclosed herein and a buffer and other components for preparing a deliverable form of the drug; and/or a device for delivering such drugs; and/or any agent for combination therapy with the compounds disclosed herein; and/or instructions for treating the disease packaged with the drug. The instructions may be fixed in any tangible medium, such as printed paper, or magnetic or optical media readable by a computer, or may refer to instructions in a remote computer data source, such as a World Wide Web page accessible via the Internet.

「治療有效量」意指有效治療或預防所治療受試者的已有症狀的發展或減輕已有症狀的量。尤其根據本文所提供的詳細揭露，有效量的確定完全在熟習此項技術者的能力範圍內。通常，「治療有效劑量」係指導致實現所需效果的化合物的量。例如，在一個較佳的實施方式中，與對照相比，治療有效量的本文所揭露的化合物將KRAS活性降低至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%或至少90%。"Therapeutically effective amount" means an amount that is effective to treat or prevent the development of existing symptoms or to alleviate existing symptoms in the treated subject. Determination of an effective amount is well within the ability of one skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a "therapeutically effective amount" refers to the amount of a compound that results in a desired effect. For example, in a preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KRAS activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% as compared to a control.

所投與的化合物的量可以取決於所治療的受試者、受試者的年齡、健康狀況、性別及體重、並行治療（若存在）的種類、病情的嚴重程度、所需效果的性質、治療的方式及頻率以及開處方醫師的判斷。給藥頻率亦可以取決於對動脈氧分壓的藥效學作用。然而，可以根據個別受試者調整最較佳的劑量，如熟習此項技術者所理解並且不經過度實驗即可確定的。這通常包括調整標準劑量（例如，若患者體重低，則減小劑量）。The amount of compound administered may depend on the subject being treated, the subject's age, health, sex, and weight, the type of concurrent treatment (if any), the severity of the condition, the nature of the desired effect, the manner and frequency of treatment, and the judgment of the prescribing physician. The frequency of dosing may also depend on the pharmacodynamic effect on arterial oxygen partial pressure. However, the optimal dosage may be adjusted for the individual subject, as understood by those skilled in the art and can be determined without undue experimentation. This generally involves adjusting the standard dosage (e.g., reducing the dosage if the patient is of low weight).

雖然個體需求不同，但化合物的有效量的最佳範圍的確定係在本領域技術範圍的。對於在本文所鑒別的病症及障礙的治癒性或預防性治療中投與人類，例如，本發明的化合物的典型劑量可以是約0.05 mg/kg/天至約50 mg/kg/天，例如至少0.05 mg/kg、至少0.08 mg/kg、至少0.1 mg/kg、至少0.2 mg/kg、至少0.3 mg/kg、至少0.4 mg/kg或至少0.5 mg/kg，並且較佳的是50 mg/kg或更少、40 mg/kg或更少、30 mg/kg或更少、20 mg/kg或更少或10 mg/kg或更少，例如，其可以是約2.5 mg/天（0.5 mg/kg x 5 kg）至約5000 mg/天（50 mg/kg x 100 kg）。例如，化合物的劑量可以是約0.1 mg/kg/天至約50 mg/kg/天、約0.05 mg/kg/天至約10 mg/kg/天、約0.05 mg/kg/天至約5 mg/kg/天、約0.05 mg/kg/天至約3 mg/kg/天、約0.07 mg/kg/天至約3 mg/kg/天、約0.09 mg/kg/天至約3 mg/kg/天、約0.05 mg/kg/天至約0.1 mg/kg/天、約0.1 mg/kg/天至約1 mg/kg/天、約1 mg/kg/天至約10 mg/kg/天、約1 mg/kg/天至約5 mg/kg/天、約1 mg/kg/天至約3 mg/kg/天、約3 mg/天至約500 mg/天、約5 mg/天至約250 mg/天、約10 mg/天至約100 mg/天、約3 mg/天至約10 mg/天或約100 mg/天至約250 mg/天。此類劑量能以單一劑量來投與，或者可以將其分為多個劑量。使用 KRAS G12C 抑制劑的方法 While individual needs vary, determination of optimal ranges of effective amounts of the compounds is within the skill of the art. For administration to humans in the therapeutic or prophylactic treatment of the conditions and disorders identified herein, for example, a typical dosage of a compound of the invention can be about 0.05 mg/kg/day to about 50 mg/kg/day, such as at least 0.05 mg/kg, at least 0.08 mg/kg, at least 0.1 mg/kg, at least 0.2 mg/kg, at least 0.3 mg/kg, at least 0.4 mg/kg, or at least 0.5 mg/kg, and preferably 50 mg/kg or less, 40 mg/kg or less, 30 mg/kg or less, 20 mg/kg or less, or 10 mg/kg or less, for example, it can be about 2.5 mg/day (0.5 mg/kg x 5 kg) to about 5000 mg/day (50 mg/kg x 100 kg). For example, the dosage of the compound can be about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.05 mg/kg/day to about 10 mg/kg/day, about 0.05 mg/kg/day to about 5 mg/kg/day, about 0.05 mg/kg/day to about 3 mg/kg/day, about 0.07 mg/kg/day to about 3 mg/kg/day, about 0.09 mg/kg/day to about 3 mg/kg/day, about 0.05 mg/kg/day to about 0.1 mg/kg/day, about 0.1 mg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 5 mg/kg/day, about 1 mg/kg/day to about 3 mg/kg/day, about 3 mg/day to about 500 mg/day, about 5 mg/day to about 250 mg/day, about 10 mg/day to about 100 mg/day, about 3 mg/day to about 10 mg/day, or about 100 mg/day to about 250 mg/day. Such dosages can be administered in a single dose, or they can be divided into multiple doses. Methods of using KRAS G12C inhibitors

本揭露提供了抑制RAS介導的細胞信號傳導之方法，該方法包括使細胞與有效量的一種或多種本文所揭露的化合物接觸。對RAS介導的訊息傳導的抑制可以藉由本領域已知的眾多種方式來評估及證實。非限制性實例包括顯示以下項：(a) RAS的GTP酶活性的降低；(b) GTP結合親和性的降低或GDP結合親和性的增加；(c) GTP的K解離的增加或GDP的K解離的減小；(d) RAS途徑中下游的信號傳導轉導分子水平的降低，例如pMEK、pERK或pAKT水平的降低；及/或 (e) RAS複合物與下游信號傳導分子（包括但不限於Raf）的結合的降低。可以利用套組及市售測定來確定上述項中的一種或多種。The present disclosure provides a method for inhibiting RAS-mediated cell signaling, the method comprising contacting a cell with an effective amount of one or more compounds disclosed herein. Inhibition of RAS-mediated signaling can be assessed and confirmed by a variety of methods known in the art. Non-limiting examples include showing the following: (a) a decrease in the GTPase activity of RAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K dissociation of GTP or a decrease in K dissociation of GDP; (d) a decrease in the level of downstream signaling transduction molecules in the RAS pathway, such as a decrease in the level of pMEK, pERK or pAKT; and/or (e) a decrease in the binding of RAS complexes to downstream signaling molecules (including but not limited to Raf). One or more of the above items can be determined using kits and commercially available assays.

本揭露亦提供了使用本揭露的化合物或藥物組成物治療疾病病症的方法，該等疾病病症包括但不限於受累於G12C KRAS、HRAS或NRAS突變的病症（例如，癌症）。The present disclosure also provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions (e.g., cancer) affected by G12C KRAS, HRAS or NRAS mutations.

在一些實施方式中，提供了治療癌症之方法，該方法包括向有需要的受試者投與有效量的任一種包含如本文所揭露的化合物的前述藥物組成物。在一些實施方式中，癌症係由KRAS、HRAS或NRAS G12C突變介導的。在各個實施方式中，癌症係胰臟癌、結直腸癌或肺癌。在一些實施方式中，癌症係膽囊癌、甲狀腺癌及膽管癌。In some embodiments, a method of treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound as disclosed herein. In some embodiments, the cancer is mediated by a KRAS, HRAS, or NRAS G12C mutation. In various embodiments, the cancer is pancreatic cancer, colorectal cancer, or lung cancer. In some embodiments, the cancer is gallbladder cancer, thyroid cancer, and bile duct cancer.

在一些實施方式中，本揭露提供了治療有需要的受試者的障礙的方法，其中該方法包括確定受試者是否具有KRAS、HRAS或NRAS G12C突變，以及若確定受試者具有KRAS、HRAS或NRAS G12C突變，則向受試者投與治療有效劑量的至少一種如本文所揭露的化合物或其藥學上可接受的鹽。In some embodiments, the disclosure provides a method of treating a disorder in a subject in need thereof, wherein the method comprises determining whether the subject has a KRAS, HRAS or NRAS G12C mutation, and if the subject is determined to have a KRAS, HRAS or NRAS G12C mutation, administering to the subject a therapeutically effective amount of at least one compound as disclosed herein or a pharmaceutically acceptable salt thereof.

所揭露化合物抑制非錨定依賴性細胞生長，並且因此具有抑制腫瘤轉移的潛力。因此，本揭露的另一個實施方式提供了抑制腫瘤轉移之方法，該方法包括投與有效量的本文所揭露的化合物。The disclosed compounds inhibit anchor-independent cell growth and thus have the potential to inhibit tumor metastasis. Therefore, another embodiment of the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount of the compound disclosed herein.

亦已經在血液惡性腫瘤（例如，影響血液、骨髓及/或淋巴結的癌症）中鑒別出KRAS、HRAS或NRAS G12C突變。因此，某些實施方式關於將所揭露化合物（例如，呈藥物組成物形式）投與需要治療血液惡性腫瘤的患者。此類惡性腫瘤包括但不限於白血病及淋巴瘤。例如，當前所揭露的化合物可以用於治療例如以下等疾病：急性淋巴細胞性白血病（ALL）、急性髓性白血病（AML）、慢性淋巴球性白血病（CLL）、小淋巴細胞淋巴瘤（SLL）、慢性骨髓性白血病（CML）、急性單核細胞白血病（AMoL）及/或其他白血病。在其他實施方式中，該等化合物可用於治療淋巴瘤，例如所有亞型的何杰金氏淋巴瘤或非何杰金氏淋巴瘤。在各個實施方式中，該等化合物可用於治療漿細胞惡性腫瘤，例如多發性骨髓瘤、外膜細胞淋巴瘤及華氏巨球蛋白血症。KRAS, HRAS or NRAS G12C mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow and/or lymph nodes). Therefore, certain embodiments relate to administering the disclosed compounds (e.g., in the form of a pharmaceutical composition) to a patient in need of treatment for a hematological malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the presently disclosed compounds can be used to treat diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and/or other leukemias. In other embodiments, the compounds can be used to treat lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma. In various embodiments, the compounds can be used to treat plasma cell malignancies, such as multiple myeloma, adrenal cell lymphoma, and Waldenstrom's macroglobulinemia.

確定腫瘤或癌症是否包含G12C KRAS、HRAS或NRAS突變可以藉由評估編碼KRAS、HRAS或NRAS蛋白的核苷酸序列，藉由評估KRAS、HRAS或NRAS蛋白的胺基酸序列，或藉由評估推定的KRAS、HRAS或NRAS突變體蛋白的特徵來進行。野生型人類KRAS、HRAS或NRAS的序列係本領域已知的（例如，登錄號NP203524）。Determining whether a tumor or cancer contains a G12C KRAS, HRAS or NRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS, HRAS or NRAS protein, by evaluating the amino acid sequence of the KRAS, HRAS or NRAS protein, or by evaluating the characteristics of a putative KRAS, HRAS or NRAS mutant protein. The sequence of wild-type human KRAS, HRAS or NRAS is known in the art (e.g., Accession No. NP203524).

偵測KRAS、HRAS或NRAS核苷酸序列中的突變的方法係熟習此項技術者已知的。該等方法包括但不限於聚合酶鏈式反應-限制性片段長度多態性（PCR-RFLP）測定、聚合酶鏈式反應-單鏈構象多態性（PCR-SSCP）測定、即時PCR測定、PCR測序、突變體等位基因特異性PCR擴增（MASA）測定、直接測序、引物延伸反應、電泳、寡核苷酸連接測定、雜交測定、TaqMan測定、SNP基因分型測定、高解析度熔解測定及微陣列分析。在一些實施方式中，藉由即時PCR針對G12C KRAS、HRAS或NRAS突變評價樣本。在即時PCR中，使用對KRAS、HRAS或NRAS G12C突變具特異性的螢光探針。在突變存在時，探針結合並偵測到螢光。在一些實施方式中，使用KRAS、HRAS或NRAS基因中的特定區域（例如，外顯子2及/或外顯子3）的直接測序方法來鑒別KRAS、HRAS或NRAS G12C突變。這種技術將鑒別所測序區域中所有可能的突變。Methods for detecting mutations in KRAS, HRAS or NRAS nucleotide sequences are known to those skilled in the art. Such methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for G12C KRAS, HRAS or NRAS mutations by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRAS, HRAS or NRAS G12C mutation is used. In the presence of the mutation, the probe binds and fluorescence is detected. In some embodiments, a direct sequencing method of a specific region (e.g., exon 2 and/or exon 3) in the KRAS, HRAS or NRAS gene is used to identify the KRAS, HRAS or NRAS G12C mutation. This technique will identify all possible mutations in the sequenced region.

偵測KRAS、HRAS或NRAS蛋白中的突變的方法係熟習此項技術者已知的。該等方法包括但不限於使用對突變體蛋白具特異性的結合劑（例如，抗體）偵測KRAS、HRAS或NRAS突變體、蛋白質電泳及蛋白質印跡法、以及直接肽測序。Methods for detecting mutations in KRAS, HRAS or NRAS proteins are known to those skilled in the art. Such methods include, but are not limited to, detecting KRAS, HRAS or NRAS mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

確定腫瘤或癌症是否包含G12C KRAS、HRAS或NRAS突變的方法可以使用多種樣本。在一些實施方式中，樣本取自患有腫瘤或癌症的受試者。在一些實施方式中，樣本係新鮮腫瘤/癌症樣本。在一些實施方式中，樣本係冷凍腫瘤/癌症樣本。在一些實施方式中，樣本係福馬林固定的石蠟包埋的樣本。在一些實施方式中，樣本係循環腫瘤細胞（CTC）樣本。在一些實施方式中，將樣本加工為細胞裂解物。在一些實施方式中，將樣本加工為DNA或RNA。Methods for determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

本揭露亦關於治療哺乳動物的過度增生障礙之方法，該方法包括向所述哺乳動物投與治療有效量的如本文所揭露的化合物或其藥學上可接受的鹽。在一些實施方式中，所述方法涉及治療患有癌症的受試者，該癌症係例如急性髓樣白血病、青少年癌症、兒童腎上腺皮質癌、AIDS相關癌症（例如，淋巴瘤及卡波西氏肉瘤）、肛門癌、闌尾癌、星形細胞瘤、非典型類畸胎瘤、基底細胞癌、膽管癌、膀胱癌、骨癌、腦幹細胞神經膠質瘤、腦瘤、乳癌、支氣管腫瘤、柏基特氏淋巴瘤、類癌瘤、非典型類畸胎瘤、胚胎瘤、胚細胞瘤、原發性淋巴瘤、子宮頸癌、兒童癌症、脊索瘤、心臟腫瘤、慢性淋巴球性白血病（CLL）、慢性骨髓性白血病（CML）、慢性骨髓增生性障礙、結腸癌、結直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、肝外導管原位癌（DCIS）、胚胎瘤、CNS癌症、子宮內膜癌、室管膜瘤、食管癌、鼻腔神經膠質瘤、ewing氏肉瘤、顱外胚細胞瘤、性腺外胚細胞瘤、眼癌、骨纖維組織細胞瘤、膽囊癌、胃癌、胃腸類癌瘤、胃腸道間質瘤（GIST）、胚細胞瘤、妊娠滋養細胞瘤、毛細胞白血病、頭頸癌、心臟癌症、肝癌、何杰金氏淋巴瘤、下咽癌、眼內黑色素瘤、胰島細胞瘤、胰腺神經內分泌腫瘤、腎癌、喉癌、嘴唇及口腔癌、肝癌、小葉原位癌（LCIS）、肺癌、淋巴瘤、轉移性伴隱匿性原發性鱗狀頸癌、中線癌、口腔癌、多發性內分泌瘤綜合症、多發性骨髓瘤/漿細胞腫瘤、蕈狀肉芽腫、骨髓增生異常綜合症、骨髓化生不良/骨髓增生腫瘤、多發性骨髓瘤、梅克爾細胞癌、惡性間皮瘤、骨惡性纖維組織細胞瘤及骨肉瘤、鼻腔及副鼻竇癌、鼻咽癌、神經母細胞瘤、非何杰金氏淋巴瘤、非小細胞肺癌（NSCLC）、口癌、嘴唇及口腔癌、口咽癌、卵巢癌、胰臟癌、乳頭狀瘤病、副神經節瘤、副鼻竇及鼻腔癌、副甲狀腺癌、陰莖癌、咽癌、胸膜肺母細胞瘤、原發性中樞神經系統（CNS）淋巴瘤、前列腺癌、直腸癌、移行細胞癌、視網膜母細胞瘤、橫紋肌肉瘤、涎腺癌、皮膚癌、胃（stomach/gastric）癌、小細胞肺癌、小腸癌、軟組織肉瘤、T細胞淋巴瘤、睾丸癌、咽喉癌、胸腺瘤及胸腺癌、甲狀腺癌、腎盂及輸尿管移行細胞癌、滋養細胞瘤、兒童罕見癌症、尿道癌、子宮肉瘤、陰道癌、外陰癌或病毒誘發的癌症。在一些實施方式中，所述方法涉及治療非癌性過度增生障礙，例如皮膚的良性增生（例如，銀屑病）、再狹窄或前列腺（例如，良性前列腺肥大（BPH））。The disclosure also relates to methods of treating a hyperproliferative disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves treating a subject having cancer, such as acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, coccygeal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem cell neuroglioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic bone Myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, cranio-pharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neurocolloid, Ewing's sarcoma, cranial ectodermal tumor, gonadal ectodermal tumor, eye cancer, osteofibroblastic cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic nerve Endocrine tumors, Kidney cancer, Laryngeal cancer, Lip and oral cancer, Liver cancer, Lobular carcinoma in situ (LCIS), Lung cancer, Lymphoma, Metastatic occult primary squamous cell carcinoma, Midline cancer, Oral cancer, Multiple endocrine neoplasia syndrome, Multiple myeloma/plasma cell neoplasia, Mycosis fungoides, Myeloproliferative syndrome, Myelodysplastic/myeloproliferative neoplasm, Multiple myeloma, Merkel cell carcinoma, Malignant mesothelioma, Malignant fibromyoma of bone and osteosarcoma, Nasal and paranasal sinus cancer, Nasopharyngeal cancer, Neuroblastoma, Non-Hodgkin's lymphoma, Non-small cell lung cancer (NSCLC), Oral cancer, Lip and oral cancer, Oropharyngeal cancer, Ovarian cancer, Pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (stomach/gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastoma, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers. In some embodiments, the methods involve treating a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or the prostate (e.g., benign prostatic hypertrophy (BPH)).

在一些實施方式中，治療方法涉及治療肺癌，該等方法包括向有需要的受試者投與有效量的任一種上述化合物（或包含該化合物的藥物組成物）。在某些實施方式中，肺癌係非小細胞肺癌（NSCLC），例如腺癌、鱗狀細胞肺癌或大細胞肺癌。在一些實施方式中，肺癌係小細胞肺癌。可用所揭露化合物治療的其他肺癌包括但不限於腺瘤、類癌瘤及未分化癌。In some embodiments, the treatment method involves treating lung cancer, comprising administering an effective amount of any of the above compounds (or a pharmaceutical composition comprising the compound) to a subject in need thereof. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. Other lung cancers that can be treated with the disclosed compounds include, but are not limited to, adenomas, carcinoid tumors, and undifferentiated carcinomas.

本揭露進一步提供了調節G12C突變體KRAS、HRAS或NRAS蛋白活性的方法，其藉由使該蛋白質與有效量的本揭露的化合物接觸來進行。調節可以是抑制或激活蛋白質活性。在一些實施方式中，本揭露提供了抑制蛋白質活性的方法，其藉由使G12C突變體KRAS、HRAS或NRAS蛋白與有效量的本揭露的化合物在溶液中接觸來進行。在一些實施方式中，本揭露提供了抑制G12C突變體KRAS、HRAS或NRAS蛋白活性的方法，其藉由接觸表現感興趣的蛋白質的細胞、組織或器官來進行。在一些實施方式中，本揭露提供了在包括但不限於齧齒動物及哺乳動物（例如，人類）的受試者中抑制蛋白質活性的方法，其藉由向該受試者投與有效量的本揭露的化合物來進行。在一些實施方式中，調節百分比超過25%、30%、40%、50%、60%、70%、80%或90%。在一些實施方式中，抑制百分比超過25%、30%、40%、50%、60%、70%、80%或90%。The present disclosure further provides a method for regulating the activity of a G12C mutant KRAS, HRAS or NRAS protein by contacting the protein with an effective amount of a compound disclosed herein. Regulation may be inhibition or activation of protein activity. In some embodiments, the present disclosure provides a method for inhibiting protein activity by contacting a G12C mutant KRAS, HRAS or NRAS protein with an effective amount of a compound disclosed herein in a solution. In some embodiments, the present disclosure provides a method for inhibiting the activity of a G12C mutant KRAS, HRAS or NRAS protein by contacting a cell, tissue or organ expressing the protein of interest. In some embodiments, the present disclosure provides a method for inhibiting protein activity in a subject including but not limited to rodents and mammals (e.g., humans) by administering an effective amount of a compound disclosed herein to the subject. In some embodiments, the percent modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percent inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

在一些實施方式中，本揭露提供了抑制細胞中的KRAS、HRAS或NRAS G12C活性的方法，其藉由使所述細胞與一定量的本揭露的化合物接觸來進行，該量足以抑制所述細胞中KRAS、HRAS或NRAS G12C的活性。在一些實施方式中，本揭露提供了抑制組織中的KRAS、HRAS或NRAS G12C活性的方法，其藉由使所述組織與一定量的本揭露的化合物接觸來進行，該量足以抑制所述組織中KRAS、HRAS或NRAS G12C的活性。在一些實施方式中，本揭露提供了抑制生物體中的KRAS、HRAS或NRAS G12C活性的方法，其藉由使所述生物體與一定量的本揭露的化合物接觸來進行，該量足以抑制所述生物體中KRAS、HRAS或NRAS G12C的活性。在一些實施方式中，本揭露提供了抑制動物中的KRAS、HRAS或NRAS G12C活性的方法，其藉由使所述動物與一定量的本揭露的化合物接觸來進行，該量足以抑制所述動物中KRAS、HRAS或NRAS G12C的活性。在一些實施方式中，本揭露提供了抑制哺乳動物中的KRAS、HRAS或NRAS G12C活性的方法，其藉由使所述哺乳動物與一定量的本揭露的化合物接觸來進行，該量足以抑制所述哺乳動物中KRAS、HRAS或NRAS G12C的活性。在一些實施方式中，本揭露提供了抑制人類中的KRAS、HRAS或NRAS G12C活性的方法，其藉由使所述人類與一定量的本揭露的化合物接觸來進行，該量足以抑制所述人類中KRAS、HRAS或NRAS G12C的活性。本揭露提供了治療需要這種治療的受試者的由KRAS、HRAS或NRAS G12C活性介導的疾病的方法。組合療法 In some embodiments, the disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in a cell, which is performed by contacting the cell with a certain amount of a compound of the disclosure, which is sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the cell. In some embodiments, the disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in a tissue, which is performed by contacting the tissue with a certain amount of a compound of the disclosure, which is sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the tissue. In some embodiments, the disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in an organism, which is performed by contacting the organism with a certain amount of a compound of the disclosure, which is sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the organism. In some embodiments, the disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in an animal by contacting the animal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the animal. In some embodiments, the disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in a mammal by contacting the mammal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the mammal. In some embodiments, the disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in a human by contacting the human with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the human. The present disclosure provides methods for treating a disease mediated by KRAS, HRAS or NRAS G12C activity in a subject in need of such treatment .

本揭露亦提供了用於組合療法之方法，其中將已知可調節其他途徑或相同途徑的其他組分的藥劑，或甚至靶標酶的重疊組與本揭露的化合物或其藥學上可接受的鹽組合使用。在一方面，這種療法包括但不限於本揭露的一種或多種化合物與化學治療劑、治療性抗體及輻射治療的組合，以提供協同或累加的治療效果。The disclosure also provides methods for combination therapy, in which agents known to modulate other pathways or other components of the same pathway, or even overlapping groups of target enzymes, are used in combination with the compounds of the disclosure or pharmaceutically acceptable salts thereof. In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects.

許多化學治療劑目前係本領域已知的，並且可以與本揭露的化合物組合使用。在一些實施方式中，化學治療劑選自由以下組成之群組：有絲分裂抑制劑、烷基化劑、抗代謝藥、嵌入抗生素、生長因子抑制劑、細胞週期抑制劑、酶、拓撲異構酶抑制劑、生物反應修飾劑、抗激素藥、血管發生抑制劑及抗雄激素。非限制性實例係化學治療劑、細胞毒性劑及非肽小分子，例如Gleevec®（甲磺酸伊馬替尼）、Kyprolis®（卡非佐米（carfilzomib））、Velcade®（硼替佐米（bortezomib））、Casodex（比卡魯胺（bicalutamide））、Iressa®（吉非替尼（gefitinib））、Venclexta^TM （維納妥拉）及Adriamycin^TM （多柔比星（docorubicin））以及多種化學治療劑。化學治療劑的非限制性實例包括烷基化劑，例如噻替派及環磷醯胺（Cytoxan^TM ）；烷基磺酸酯，例如白消安（busulfan）、英丙舒凡（improsulfan）及哌泊舒凡（piposulfan）；氮丙啶，例如苯佐替哌（benzodopa）、卡波醌（carboquone）、美妥替哌（meturedopa）及烏瑞替哌（uredopa）；乙烯亞胺及甲基蜜胺（methylamelamine），包括六甲蜜胺、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺（triethylenethiophosphaoramide）及三羥甲基蜜胺（trimethylolomelamine）；氮芥，例如苯丁酸氮芥、萘氮芥、氯環磷醯胺、雌氮芥、異環磷醯胺、二氯甲基二乙胺、鹽酸甲氧氮芥（mechlorethamine oxide hydrochloride）、美法侖（melphalan）、新恩比興（novembichin）、苯芥膽甾醇（phenesterine）、潑尼莫司汀（prednimustine）、曲磷胺（trofosfamide）、尿嘧啶氮芥；亞硝基脲，例如卡莫司汀（carmustine）、氯脲黴素（chlorozotocin）、福莫司汀（fotemustine）、洛莫司汀（lomustine）、尼莫司汀（nimustine）、雷莫司汀（ranimustine）；抗生素，例如阿克拉黴素（aclacinomysin）、放線菌素（actinomycin）、安麯黴素（authramycin）、重氮絲胺酸、博來黴素、放線菌素（cactinomycin）、卡奇黴素（calicheamicin）、卡柔比星（carabicin）、洋紅黴素（carminomycin）、嗜癌菌素（carzinophilin）、Casodex^TM 、色黴素（chromomycins）、更生黴素（dactinomycin）、道諾黴素（daunorubicin）、地托比星（detorubicin）、6-重氮基-5-側氧基-L-正白胺酸、多柔比星（doxorubicin）、表柔比星（epirubicin）、依索比星（esorubicin）、伊達比星（idarubicin）、麻西羅黴素（marcellomycin）、絲裂黴素（mitomycins）、黴酚酸（mycophenolic acid）、諾加黴素（nogalamycin）、橄欖黴素（olivomycins）、培洛黴素（peplomycin）、泊非黴素（potfiromycin）、嘌呤黴素（puromycin）、三鐵阿黴素（quelamycin）、羅多比星（rodorubicin）、鏈黑菌素（streptonigrin）、鏈脲黴素（streptozocin）、殺結核菌素（tubercidin）、烏苯美司（ubenimex）、淨司他丁（zinostatin）、佐柔比星（zorubicin）；抗代謝藥，例如胺甲喋呤及5-氟尿嘧啶（5-FU）；葉酸類似物，例如二甲葉酸（denopterin）、胺甲喋呤、蝶羅呤（pteropterin）、三甲曲沙（trimetrexate）；嘌呤類似物，例如氟達拉濱（fludarabine）、6-巰嘌呤、硫咪嘌呤、硫鳥嘌呤；嘧啶類似物，例如安西他濱（azacitidine）、阿紮胞苷（azacitidine）、6-氮雜尿苷、卡莫氟（carmofur）、阿糖胞苷（cytarabine）、二去氧尿苷（dideoxyuridine）、去氧氟尿苷（doxifluridine）、依諾他濱（enocitabine）、氟尿苷（floxuridine），雄激素例如卡普睾酮（calusterone）、屈他雄酮丙酸酯（dromostanolone propionate）、環硫雄醇（epitiostanol）、美雄烷（mepitiostane）、睾內酯（testolactone）；抗腎上腺藥，例如胺魯米特（aminoglutethimide）、米托坦（mitotane）、曲洛司坦（trilostane）；葉酸補充劑，例如亞葉酸（frolinic acid）；醋葡醛內酯（aceglatone）；醛磷醯胺糖苷；胺基乙醯丙酸；安吖啶（amsacrine）；倍曲布西（bestrabucil）；比生群（bisantrene）；依達曲沙（edatraxate）；地磷醯胺（defofamine）；秋水仙胺（demecolcine）；地吖醌（diaziquone）；依氟鳥胺酸（elfomithine）；依利醋銨（elliptinium acetate）；依託格魯（etoglucid）；硝酸鎵；羥基脲；香菇多糖（lentinan）；氯尼達明（lonidamine）；米托胍腙（mitoguazone）；米托蒽醌（mitoxantrone）；莫哌達醇（mopidamol）；硝胺丙吖啶（nitracrine）；噴司他丁（pentostatin）；蛋胺氮芥（phenamet）；吡柔比星（pirarubicin）；鬼臼酸（podophyllinic acid）；2-乙基醯肼；丙卡巴肼（procarbazine）；PSK；丙亞胺；西佐喃（sizofiran）；鍺螺胺（spirogermanium）；細交鏈孢菌酮酸（tenuazonic acid）；三亞胺醌（triaziquone）；2,2’,2’’-三氯三乙胺；烏拉坦（urethan）；長春地辛（vindesine）；達卡巴𠯤（dacarbazine）；甘露莫司汀（mannomustine）；二溴甘露醇（mitobronitol）；二溴衛矛醇（mitolactol）；哌泊溴烷（pipobroman）；加賽特辛（gacytosine）；阿拉伯糖苷（「Ara-C」）；環磷醯胺（cyclophosphamide）；噻替派（thiotepa）；紫杉烷，例如紫杉酚及多西他賽（docetaxel）；視黃酸；埃斯波黴素（esperamicin）；卡培他濱（capecitabine）；以及上述任何一種的藥學上可接受的鹽、酸或衍生物。Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds disclosed herein. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules, such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), Venclexta ^™ (venatoclax), and Adriamycin ^™ (docorubicin), as well as various chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide (Cytoxan ^™ ); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylamelamines including hexamethylmelamine, triethylmelamine, triethylphosphatamide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, naphthyl mustard, chlorambucil, estramustamide, isophosphatamide, dichloromethyldiethylamine, mechlorethamine oxide hydrochloride), melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, stine, ranimustine; antibiotics such as aclacinomysin, actinomycin, authramycin, diazoserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex ^TM , chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolic drugs such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, amine Mettrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-thiazolidine, thiopurine, thioguanine; pyrimidine analogs such as azacitidine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate propionate, epitiostanol, mepitiostane, testolactone; adrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycosides; aminoacetylpropionic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK; aprotinin; sizofiran; spirogermanium; tenuazonic acid acid); triaziquone; 2,2',2''-trichlorotriethylamine;urethan;vindesine;dacarbazine;mannomustine;mitobronitol;mitolactol;pipobroman;gacytosine; arabinoside ("Ara-C");cyclophosphamide;thiotepa; taxanes such as paclitaxel and docetaxel; retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.

作為適合的化學治療性細胞調理劑亦包括用於調節或抑制激素對腫瘤的作用的抗激素劑，例如抗雌激素藥，包括例如他莫昔芬（tamoxifen）（Nolvadex^TM ）、雷洛昔芬（raloxifene）、芳香酶抑制性4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬（trioxifene）、可莫昔芬（keoxifene）、LY 117018、奧那司酮（onapristone）及托瑞米芬（toremifene）（法樂通（Fareston））；及抗雄激素藥，例如氟他胺（flutamide）、尼魯米特（nilutamide）、比卡魯胺（bicalutamide）、亮丙瑞林（leuprolide）及戈舍瑞林（goserelin）；苯丁酸氮芥；吉西他濱（gemcitabine）；6-硫鳥嘌呤；巰嘌呤；胺甲喋呤；鉑類似物，例如順鉑及卡鉑；長春鹼；鉑；依託泊苷（etoposide）（VP-16）；異環磷醯胺（ifosfamide）；絲裂黴素（mitomycin）C；米托蒽醌（mitoxantrone）；長春新鹼（vincristine）；長春瑞濱（vinorelbine）；諾維本（navelbine）；諾安托（novantrone）；替尼泊苷（teniposide）；道諾黴素（daunomycin）；胺基喋呤（aminopterin）；希羅達（xeloda）；伊班膦酸鹽（ibandronate）；喜樹鹼（camptothecin）-11（CPT-11）；拓撲異構酶抑制劑RFS 2000；二氟甲基鳥胺酸（DMFO）。Suitable chemotherapeutic cell conditioning agents also include anti-hormonal agents used to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen (Nolvadex ^™ ), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and toremifene (Fareston); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; purine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); isocyclophosphamide ( ifosfamide); mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO).

若需要，本揭露的化合物或藥物組成物可以與通常開具的抗癌藥物組合使用，例如Herceptin®、Avastin®、Erbitux®、Rituxan®、Taxol®、Arimidex®、Taxotere®、ABVD、阿維金（AVICINE）、阿巴伏單抗（Abagovomab）、吖啶羧醯胺（Acridine carboxamide）、阿德木單抗（Adecatumumab）、17-N-烯丙基胺基-17-去甲氧基格爾德黴素、阿法雷丁（Alpharadin）、阿瓦昔地（Alvocidib）、3-胺基吡啶-2-甲醛胺基硫脲、胺萘非特（Amonafide）、蒽二酮（Anthracenedione）、抗CD22免疫毒素、抗腫瘤藥、抗腫瘤發生草藥（Antitumorigenic herbs）、阿帕茲醌（Apaziquone）、阿替莫德（Atiprimod）、硫唑嘌呤（Azathioprine）、貝洛替康（Belotecan）、苯達莫司汀（Bendamustine）、BIBW 2992、比立考達（Biricodar）、伯斯塔利辛（Brostallicin）、苔蘚抑素（Bryostatin）、丁硫胺酸亞碸胺（Buthionine sulfoximine）、CBV（化學療法）、花萼海綿誘癌素（Calyculin）、細胞週期非特異性抗腫瘤劑、二氯乙酸、圓皮海綿內酯（Discodermolide）、依沙蘆星（Elsamitrucin）、依諾他濱（Enocitabine）、埃博黴素（Epothilone）、艾日布林（Eribulin）、依維莫司（Everolimus）、依沙替康（Exatecan）、依昔舒林（Exisulind）、鐵銹醇（Ferruginol）、氟羅德辛（Forodesine）、磷雌酚（Fosfestrol）、ICE化學治療方案、IT-101、伊美克（Imexon）、咪喹莫特（Imiquimod）、吲哚并咔唑（Indolocarbazole）、伊羅夫文（Irofulven）、拉尼喹達（Laniquidar）、拉洛他賽（Larotaxel）、來那度胺（Lenalidomide）、硫蒽酮（Lucanthone）、勒托替康（Lurtotecan）、馬磷醯胺（Mafosfamide）、米托唑胺（Mitozolomide）、萘福昔定（Nafoxidine）、奈達鉑（Nedaplatin）、奧拉帕尼（Olaparib）、沃塔紫杉醇（Ortataxel）、PAC-1、木瓜（Pawpaw）、匹杉瓊（Pixantrone）、蛋白酶體抑制劑、蝴蝶黴素（Rebeccamycin）、瑞喹莫德（Resiquimod）、魯比特康（Rubitecan）、SN-38、鹽孢菌醯胺A（Salinosporamide A）、沙帕他濱（Sapacitabine）、斯坦福V（Stanford V）、苦馬豆素（Swainsonine）、他拉泊芬（Talaporfin）、塔利喹達（Tariquidar）、優福定（Tegafur-uracil）、特莫多（Temodar）、替司他賽（Tesetaxel）、四硝酸三鉑（Triplatin tetranitrate）、三(2-氯乙基)胺、曲沙他濱（Troxacitabine）、烏拉莫司汀（Uramustine）、瓦帝莫澤（Vadimezan）、長春氟寧（Vinflunine）、ZD6126或唑喹達（Zosuquidar）。If desired, the compounds or pharmaceutical compositions of the present disclosure can be used in combination with commonly prescribed anticancer drugs, such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldermycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde aminothiourea, Amonafide, Anthracenedione, anti-CD22 immunotoxins, antitumor drugs, antitumorigenic herbal drugs, herbs), Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine), CBV (chemotherapy), Calyculin, Cytokine-dependent Nonspecific Antineoplastic Agents, Dichloroacetic Acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE Chemotherapy, IT-101, Imexon, Imiquimod, Indolocarbazole, Irov Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome Inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A), sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

本揭露進一步關於使用本文所提供的化合物或藥物組成物與放射療法的組合在哺乳動物中抑制異常細胞生長或治療過度增生障礙的方法。施用放射療法的技術係本領域已知的，並且該等技術可以用於本文所述的組合療法中。這種組合療法中本揭露的化合物的投與可以如本文所述來確定。The present disclosure further relates to methods of inhibiting abnormal cell growth or treating hyperproliferative disorders in mammals using a combination of a compound or pharmaceutical composition provided herein and radiation therapy. Techniques for administering radiation therapy are known in the art, and such techniques can be used in the combination therapy described herein. The administration of the disclosed compound in such a combination therapy can be determined as described herein.

放射療法可以藉由若干種方法之一或方法的組合來施用，包括但不限於外射束療法、內放射療法、植入物放射、立體定位性放射外科手術、全身放射療法、放射療法及永久性或臨時性間質近距離放射療法。如本文所用，術語「近距離放射療法」係指藉由空間受限的放射性材料遞送的放射療法，該放射性材料係在腫瘤或其他增生性組織患病位點處或附近插入體內的。該術語意圖不受限制地包括暴露於放射性同位素（例如，At-211、I-131、I-125、Y-90、Re-186、Re-188、Sm-153、Bi-212、P-32及Lu的放射性同位素）。用作本揭露的細胞調理劑的適合的放射源包括固體及液體。藉由非限制性實例，放射源可以是放射性核素，例如作為固體來源的I-125、I-131、Yb-169、Ir-192，作為固體來源的I-125，或發射光子、β粒子、γ輻射或其他治療性射線的其他放射性核素。放射性材料亦可以是從一種或多種放射性核素的任何溶液（例如，I-125或I-131的溶液）製備的流體，或者放射性流體可以使用含有固體放射性核素（例如Au-198、Y-90）的小顆粒的適合的流體的漿液產生。此外，可以將一種或多種放射性核素包埋於凝膠或放射性微球中。Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, whole body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by spatially confined radioactive material that is inserted into the body at or near the site of a tumor or other proliferative tissue disease. The term is intended to include, without limitation, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radioactive sources for use as cell conditioning agents of the present disclosure include solids and liquids. By way of non-limiting example, the radioactive source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation or other therapeutic radiation. The radioactive material can also be a fluid prepared from any solution of one or more radionuclides (e.g., a solution of I-125 or I-131), or the radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides (e.g., Au-198, Y-90). In addition, one or more radionuclides can be embedded in a gel or radioactive microspheres.

本揭露的化合物或藥物組成物可以與一定量的一種或多種選自以下的物質組合使用：抗血管發生劑、訊息傳導抑制劑、抗增殖劑、糖酵解抑制劑或自體吞噬抑制劑。The compounds or pharmaceutical compositions disclosed herein can be used in combination with a certain amount of one or more substances selected from the following: anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors or autophagy inhibitors.

抗血管發生劑可以結合本揭露的化合物及本文所述的藥物組成物使用，該等抗血管發生劑係例如MMP-2（基質金屬蛋白酶2）抑制劑、MMP-9（基質金屬蛋白酶9）抑制劑及COX-11（環氧酶11）抑制劑。抗血管發生劑包括例如雷帕黴素、替西羅莫司（temsirolimus，CCI-779）、依維莫司（RAD001）、索拉非尼、舒尼替尼及貝伐單抗。有用COX-II抑制劑的實例包括阿來昔布（alecoxib）、伐地昔布及羅非昔布。有用基質金屬蛋白酶抑制劑的實例描述於以下專利中：WO 96/33172、WO 96/27583、歐洲專利公開案EP0818442、歐洲專利公開案EP1004578、WO 98/07697、WO 98/03516、WO 98/34918、WO 98/34915、WO 98/33768、WO 98/30566、歐洲專利公開案606046、歐洲專利公開案931 788、WO 90/05719、WO 99/52910、WO 99/52889、WO 99/29667、WO 1999007675、歐洲專利公開案EP1786785、歐洲專利公開案號EP1181017、美國公開案US20090012085、美國公開案US5863 949、美國公開案US5861 510及歐洲專利公開案EP0780386，將所有該等專利藉由引用以其整體併入本文。較佳的MMP-2及MMP-9抑制劑係具有極小或無抑制MMP-1的活性的那些。更較佳的是相對於其他基質金屬蛋白酶（即，MAP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12及MMP-13）選擇性抑制MMP-2及/或AMP-9的那些。可用於本揭露中的MMP抑制劑的一些具體實例係AG-3340、RO 32-3555及RS 13-0830。Anti-angiogenic agents can be used in combination with the compounds disclosed herein and the pharmaceutical compositions described herein, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors. Anti-angiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in the following patents: WO 96/33172, WO 96/27583, European Patent Publication EP0818442, European Patent Publication EP1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, European Patent Publication 606046, European Patent Publication 931 788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 1999007675, European Patent Publication EP1786785, European Patent Publication No. EP1181017, U.S. Publication US20090012085, U.S. Publication US5863949, U.S. Publication US5861510 and European Patent Publication EP0780386, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity in inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and/or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors that can be used in the present disclosure are AG-3340, RO 32-3555, and RS 13-0830.

本發明化合物亦可以用於與其他抗瘤劑的共同療法中，該等其他抗瘤劑係例如醋孟南（acemannan）、阿柔比星、阿地介白素、阿侖單抗（alemtuzumab）、阿利維A酸（alitretinoin）、六甲蜜胺、胺磷汀、胺基乙醯丙酸、胺柔比星、安吖啶、阿那格雷、阿那曲唑、ANCER、安西司亭（ancestim）、阿加來必（ARGLABIN）、三氧化二砷、BAM 002（諾夫洛斯公司（Novelos））、貝沙羅汀（bexarotene）、比卡魯胺、溴尿苷、卡培他濱、西莫介白素、西曲瑞克、克拉屈濱、克黴唑、阿糖胞苷十八烷基磷酸鹽（cytarabine ocfosfate）、DA 3030（Dong-A）、達克珠單抗（daclizumab）、地尼介白素（denileukin diftitox）、地洛瑞林（deslorelin）、右雷佐生、地拉卓（dilazep）、多西他賽、二十二醇、度骨化醇（doxercalciferol）、去氧氟尿苷、多柔比星、溴隱亭、卡莫司汀、阿糖胞苷、氟尿嘧啶、HIT雙氯酚酸、干擾素-α、道諾黴素、多柔比星、維甲酸、依地福新、依決洛單抗、依氟鳥胺酸（eflornithine）、乙嘧替氟、表柔比星、紅血球生成素β、磷酸依託泊苷、依西美坦、依昔舒林（exisulind）、法倔唑、非格司亭（filgrastim）、非那雄胺、磷酸氟達拉濱、福美司坦（formestane）、福莫司汀、硝酸鎵、吉西他濱、吉妥珠單抗奧唑米星（gemtuzumab zogamicin）、吉美拉西（gimeracil）/奧替拉西（oteracil）/替加氟組合、格萊克濱（glycopine）、戈舍瑞林、庚鉑（heptaplatin）、人絨毛膜促性腺素、人類胎兒甲胎蛋白、伊班膦酸、伊達比星、咪喹莫特、干擾素-α、干擾素-α、天然干擾素-α-2、干擾素-α-2a、干擾素-α-2b、干擾素-α-N1、干擾素-α-_n3 、干擾素alfacon-1、干擾素α、天然干擾素β、干擾素β-1a、干擾素β-1b、干擾素γ、天然干擾素γ-1a、干擾素γ-1b、介白素-1β、碘苄胍、伊立替康、伊索拉定（irsogladine）、蘭瑞肽（lanreotide）、LC 9018（養樂多集團（Yakult））、來氟米特、來格司亭（lenograstim）、硫酸香菇多糖、來曲唑、白血球α干擾素、亮丙瑞林、左旋咪唑 + 氟尿嘧啶、利阿唑（liarozole）、洛鉑、氯尼達明、洛伐他汀、馬索羅酚、美拉胂醇、甲氧氯普胺、米非司酮、米替福新、米立司亭、錯配雙鏈RNA、米托胍腙、二溴衛矛醇、米托蒽醌、莫拉司亭（molgramostim）、那法瑞林、納洛酮 + 噴他佐辛、那托司亭（nartograstim）、奈達鉑、尼魯米特（nilutamide）、那可丁、新穎紅血球生成刺激蛋白、NSC 631570奧曲肽、奧普瑞介白素（oprelvekin）、奧沙特隆、奧沙利鉑（oxaliplatin）、紫杉酚、帕米膦酸（pamidronic acid）、培門冬酶、聚乙二醇干擾素-α-2b、木聚硫鈉（pentosan polysulfate sodium）、噴司他丁、畢西巴尼（picibanil）、吡柔比星、兔抗胸腺細胞多株抗體、聚乙二醇干擾素-α-2a、卟吩姆鈉、雷洛昔芬、雷替曲塞、拉斯伯門特（rasburiembodiment）、羥乙膦酸錸（Re 186）、RII維甲醯酚胺（RII retinamide）、利妥昔單抗、羅莫肽、來昔決南釤（153 Sm）（samarium (153 Sm) lexidronam）、沙格司亭（sargramostim）、西佐喃、索布佐生、索納明（sonermin）、氯化鍶-89、蘇拉明、他索那明（tasonermin）、他紮羅汀、替加氟、替莫泊芬（temoporfin）、替莫唑胺、替尼泊苷、四氯十氧化物、沙利度胺、胸腺法新、促甲狀腺素α、托泊替康（topotecan）、托瑞米芬、托西莫單抗（tositumomab）-碘131、曲妥珠單抗、曲奧舒凡、維甲酸、曲洛司坦、三甲曲沙、曲普瑞林、腫瘤壞死因子α、天然烏苯美司、膀胱癌疫苗、丸山（Maruyama）疫苗、黑色素瘤裂解物疫苗、戊柔比星（valrubicin）、維替泊芬、長春瑞濱、維魯利秦（VIRULIZIN）、淨司他丁斯酯（zinostatin stimalamer）或唑來膦酸；阿巴瑞克（abarelix）；AE 941（依特納公司（Aeterna））、胺莫司汀（ambamustine）、反義寡核苷酸、bcl-2（珍塔公司（Genta））、APC 8015（丹德里昂公司（Dendreon））、西妥昔單抗、地西他濱（decitabine）、德胺魯米特（dexaminoglutethimide）、地吖醌、EL 532（義隆公司（Elan））、EM 800（英杜裡奇公司（Endorecherche））、恩尿嘧啶、依他硝唑、芬維A銨（fenretinide）、非格司亭SD01（美商安進公司（Amgen））、氟維司群、加洛他濱、胃泌素17免疫原、HLA-B7基因療法（偉科公司（Vical））、粒細胞-巨噬細胞集落刺激因子、組胺二鹽酸鹽、替伊莫單抗、伊洛馬司他、IM 862（興創公司（Cytran））、介白素-2、艾潑昔芬（iproxifene）、LDI 200（米克豪公司（Milkhaus））、來立司亭（leridistim）、林妥珠單抗（lintuzumab）、CA 125 MAb（巴米拉公司（Biomira））、癌症MAb（日本製藥發展公司（Japan Pharmaceutical Development））、HER-2及Fc MAb（梅達拉公司（Medarex））、獨特型105AD7 MAb（CRC技術公司（CRC Technology））、獨特型CEA MAb（特裡萊公司（Trilex））、LYM-1-碘131 MAb（特尼殖株公司（Techniclone））、多態性上皮粘液素-釔90 MAb（安特索瑪公司（Antisoma））、馬立馬司他（marimastat）、美諾立爾、米妥莫單抗（mitumomab）、莫特沙芬釓（motexafin gadolinium）、MX 6（高德美公司（Galderma））、奈拉濱（nelarabine）、諾拉曲塞（nolatrexed）、P 30蛋白、培維索孟（pegvisomant）、培美曲塞、泊非黴素（porfiromycin）、普馬司他（prinomastat）、RL 0903（夏爾公司（Shire））、魯吡替康、沙鉑（satraplatin）、苯乙酸鈉、斯帕磷酸（sparfosic acid）、SRL 172（SR製藥公司（SR Pharma））、SU 5416（美國蘇根公司（SUGEN），現稱為輝瑞製藥公司（Pfizer, Inc.））、TA 077（田邊公司（Tanabe））、四硫鉬酸鹽、厚果糖松草鹼（thaliblastine）、血小板生成素、本紫紅素乙酯錫（tin ethyl etiopurpurin）、替拉紮明、癌症疫苗（巴米拉公司）、黑色素瘤疫苗（紐約大學（New York University））、黑色素瘤疫苗（斯隆-凱特琳研究所（Sloan Kettering Institute））、黑色素瘤腫瘤裂解物疫苗（紐約醫學院（New York Medical College））、病毒黑色素瘤細胞裂解物疫苗（皇家紐卡斯爾醫院（Royal Newcastle Hospital））或伐司朴達（valspodar）。The compounds of the present invention may also be used in combination therapy with other antineoplastic agents, such as acemannan, aclarubicin, aldeselubicin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, aminoacetyl propionic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, bromuridine, capecitabine, simucoidin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosin, doxercalciferol, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon-α, daunorubicin, doxorubicin, retinoic acid, edilfosine, edreclomab, effluridine eflornithine, ethidium bromide, epirubicin, erythropoietin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab ozogamicin zogamicin), gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, imiquimod, interferon-α, interferon-α, natural interferon-α-2, interferon-α-2a, interferon-α-2b, interferon-α-N1, interferon-α- _N3 , interferon alfacon-1, interferon alpha, natural interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1β, iodobenzylguanidine, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte interferon alpha, leuprolide, levamisole + Fluorouracil, liarozole, loplatin, lonidamine, lovastatin, masopropol, melarsoprol, metoclopramide, mifepristone, miltefosine, miristostim, mismatched double-stranded RNA, mitoguanidine, dibromosuccinol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazosin, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570, octreotide, oprelvekin, oxaliplatin, paclitaxel, pamidronate acid), pegaspargase, pegylated interferon-α-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit anti-thymocyte polyclonal antibody, pegylated interferon-α-2a, porfimbrin sodium, raloxifene, raltitrexed, rasburiembodiment, etidronate (Re 186), RII retinamide, rituximab, romotide, samarium (153 Sm) lexidronam), sargramostim, sizoran, sobuzosine, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymofasin, thyrotropin alfa, topotecan, toremide fen, tositumomab-iodine 131, trastuzumab, treoxazole, retinoic acid, trilostane, trimetrexate, triptorelin, tumor necrosis factor α, natural ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diazocone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galotabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development Co., Ltd. Development), HER-2 and Fc MAbs (Medarex), unique 105AD7 MAbs (CRC Technology), unique CEA MAbs (Trilex), LYM-1-iodine-131 MAbs (Techniclone), polymorphic epithelial mucin-yttrium-90 MAbs (Antisoma), marimastat, menolipir, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), lupinotecan, satraplatin, sodium phenylacetate, sparrosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN, now Pfizer, Inc.), TA 077 (Tanabe), molybdenum tetrathioate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Bamira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

本發明的化合物可以進一步與VEGFR抑制劑一起使用。以下專利及專利申請案中所述的其他化合物可以用於組合療法中：US 6,258,812、US 2003/0105091、WO 01/37820、US 6,235,764、WO 01/32651、US 6,630,500、US 6,515,004、US 6,713,485、US 5,521,184、US 5,770,599、US 5,747,498、WO 02/68406、WO 02/66470、WO 02/55501、WO 04/05279、WO 04/07481、WO 04/07458、WO 04/09784、WO 02/59110、WO 99/45009、WO 00/59509、WO 99/61422、US 5,990,141、WO 00/12089及WO 00/02871。The compounds of the present invention can be further used together with VEGFR inhibitors. Other compounds described in the following patents and patent applications can be used in combination therapy: US 6,258,812, US 2003/0105091, WO 01/37820, US 6,235,764, WO 01/32651, US 6,630,500, US 6,515,004, US 6,713,485, US 5,521,184, US 5,770,599, US 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO 04/05279, WO 04/07481, WO 04/07458, WO 04/09784, WO 02/59110, WO 99/45009, WO 00/59509, WO 99/61422, US 5,990,141, WO 00/12089 and WO 00/02871.

在一些實施方式中，該組合包含本發明的組成物與至少一種抗血管發生劑的組合。藥劑包括但不限於在體外以合成方式製備的化學組成物、抗體、抗原結合區、放射性核素及其組合及軛合物（conjugate）。藥劑可以是激動劑、拮抗劑、變構調節劑、毒素，或者更通常地，可以用於抑制或刺激其靶標（例如，受體或酶激活或抑制），並且由此促進細胞死亡或阻止細胞生長。In some embodiments, the combination comprises a composition of the invention in combination with at least one anti-angiogenic agent. Agents include, but are not limited to, synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof in vitro . Agents may be agonists, antagonists, allosteric modulators, toxins, or more generally, may be used to inhibit or stimulate their target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or prevent cell growth.

示例性抗血管發生劑包括ERBITUX™（IMC-C225）、KDR（激酶結構域受體）抑制劑（例如，特異性結合至激酶結構域受體的抗體及抗原結合區）、抗VEGF劑（例如，特異性結合VEGF的抗體或抗原結合區、或可溶VEGF受體或其配位基結合區）（例如AVASTIN™或VEGF-TRAP™）及抗VEGF受體劑（例如，與其特異性結合的抗體或抗原結合區）、EGFR抑制劑（例如，與其特異性結合的抗體或抗原結合區）（例如維克替比（Vectibix））帕尼單抗）、IRESSA™（吉非替尼）、TARCEVA™（厄洛替尼）、抗Ang1劑及抗Ang2劑（例如，與其或與其受體（例如Tie2/Tek）特異性結合的抗體或抗原結合區）以及抗Tie2激酶抑制劑（例如，與其特異性結合的抗體或抗原結合區）。本發明的藥物組成物亦可以包含一種或多種特異性結合生長因子並抑制生長因子的活性的藥劑（例如，抗體、抗原結合區或可溶受體），例如肝細胞生長因子（HGF，亦稱為散射因子）的拮抗劑、以及特異性結合其受體「c-met」的抗體或抗原結合區。Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF, or soluble VEGF receptors or their ligand binding regions) (e.g., AVASTIN™ or VEGF-TRAP™), and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF). binding region), EGFR inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto) (e.g., Vectibix) panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind thereto or to its receptor (e.g., Tie2/Tek)), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto). The pharmaceutical composition of the present invention may also contain one or more agents (e.g., antibodies, antigen binding regions or soluble receptors) that specifically bind to growth factors and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen binding regions that specifically bind to its receptor "c-met".

其他抗血管發生劑包括坎帕斯（Campath）、IL-8、B-FGF、Tek拮抗劑（Ceretti等人, 美國公開案號2003/0162712；美國專利號6,413,932）、抗TWEAK劑（例如，特異性結合抗體或抗原結合區，或可溶TWEAK受體拮抗劑；參見Wiley，美國專利號6,727,225）、用於拮抗整聯蛋白與其配位基的結合的ADAM去整合素結構域（Fanslow等人, 美國公開案號2002/0042368）、特異性結合抗eph受體及/或抗蝶素（ephrin）抗體或抗原結合區（美國專利號5,981,245；5,728,813；5,969,110；6,596,852；6,232,447；6,057,124及其專利族成員）及抗PDGF-BB拮抗劑（例如，特異性結合抗體或抗原結合區）以及特異性結合PDGF-BB配位基的抗體或抗原結合區及PDGFR激酶抑制劑（例如，與其特異性結合的抗體或抗原結合區）。Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., U.S. Publication No. 2003/0162712; U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., specific binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see Wiley, U.S. Patent No. 6,727,225), ADAM disintegrin domains for antagonizing the binding of integrins to their ligands (Fanslow et al., U.S. Publication No. 2002/0042368), antibodies or antigen binding regions that specifically bind to eph receptors and/or ephrins (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of their patent families), and anti-PDGF-BB antagonists (e.g., antibodies or antigen binding regions that specifically bind to PDGF-BB ligands), and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind to them).

其他抗血管發生/抗腫瘤劑包括：SD-7784（美國輝瑞公司（Pfizer））；西侖吉肽（cilengitide）（德國默克集團（Merck KGaA），EPO 770622）；哌加他尼八鈉（pegaptanib octasodium）（美國吉利德科學公司（Gilead Sciences））；阿耳法他汀（Alphastatin）（英國百克塔公司（BioActa））；M-PGA（美國賽爾基因公司（Celgene），US 5712291）；伊洛馬司他（美國愛瑞發公司（Arriva），US 5892112）；艾瑪夏尼（emaxanib）（美國輝瑞公司，US 5792783）；瓦他拉尼（vatalanib）（瑞士諾華製藥公司（Novartis））；2-甲氧基雌二醇（美國安翠梅德公司（EntreMed），現稱為CASI製藥）；TLC ELL-12（愛爾蘭義隆公司）；乙酸阿奈可他（anecortave acetate）（美國愛爾康公司（Alcon））；α-D148 Mab（美商安進公司）；CEP-7055（美國瑟法隆公司（Cephalon））；抗Vn Mab（荷蘭克魯賽爾公司（Crucell））；DAC:抗血管發生劑（加拿大康久化學公司（ConjuChem））；安吉西丁（Angiocidin）（美國英可因製藥公司（InKine Pharmaceutical））；KM-2550（日本協和發酵工業株式會社（Kyowa Hakko））；SU-0879（美國輝瑞公司）；CGP-79787（瑞士諾華製藥公司，EP 970070）；ARGENT技術（美國阿瑞雅德公司（Ariad））；YIGSR-Stealth（美國強生公司（Johnson & Johnson））；纖維蛋白原-E片段（英國百克塔公司）；血管發生抑制劑（英國三傑公司（Trigen））；TBC-1635（美國恩賽斯夫製藥公司（Encysive Pharmaceuticals））；SC-236（美國輝瑞公司）；ABT-567（美國雅培公司（Abbott））；轉移抑制素（Metastatin）（美國安翠梅德公司）；血管發生抑制劑（瑞典瑞派公司（Tripep））；乳腺絲抑蛋白（maspin）（日本創成公司（Sosei））；2-甲氧基雌二醇（美國腫瘤學公司（Oncology Sciences Corporation））；ER-68203-00（美國愛華克斯公司（IVAX））；氟草胺（美國萊恩實驗室公司（Lane Labs））；Tz-93（日本津村株式會社（Tsumura））；TAN-1120（日本武田株式會社（Takeda））；FR-111142（日本藤澤株式會社（Fujisawa），JP 02233610）；血小板因子4（美國瑞普利金公司（RepliGen），EP 407122）；血管內皮生長因子拮抗劑（丹麥波倫公司（Borean））；貝伐單抗（pINN）（美國基因泰克公司（Genentech））；血管發生抑制劑（美國蘇根公司）；XL 784（美國伊克塞利克斯公司（Exelixis））；XL 647（美國伊克塞利克斯公司）；第二代MAb α5β3整聯蛋白（美國應用分子進化基金會（Applied Molecular Evolution）及美國英商梅迪繆思有限公司（MedImmune））；視網膜病變的基因療法（英國牛津生物醫藥公司（Oxford BioMedica））；鹽酸恩紮妥林（enzastaurin hydrochloride）（USAN）（美國禮來公司（Lilly））；CEP 7055（美國瑟法隆公司及法國賽諾菲聖德拉堡集團（Sanofi-Synthelabo））；BC 1（義大利熱那亞癌症研究所（Genoa Institute of Cancer Research））；血管發生抑制劑（澳大利亞沃奇米亞公司（Alchemia））；VEGF拮抗劑（美國再生元公司（Regeneron））；rBPI 21及BPI衍生的抗血管發生劑（美國逍馬公司（XOMA））；PI 88（澳大利亞普健公司（Progen））；西侖吉肽（pINN）（德國默克集團；德國慕尼克技術大學（Munich Technical University），美國斯克裡普斯診所及研究基金會（Scripps Clinic and Research Foundation））；西妥昔單抗（INN）（法國安萬特公司（Aventis））；AVE 8062（日本味之素公司（Ajinomoto））；AS 1404（紐西蘭癌症研究實驗室（Cancer Research Laboratory））；SG 292（美國泰利奧斯公司（Telios））；內皮抑素（美國波士頓兒童醫院（Boston Childrens Hospital））；ATN 161（美國阿特紐公司（Attenuon））；血管抑素（美國波士頓兒童醫院）；2-甲氧基雌二醇（美國波士頓兒童醫院）；ZD 6474（英國阿斯利康公司（AstraZeneca））；ZD 6126（英國安吉奧金尼製藥公司（Angiogene Pharmaceuticals））；PPI 2458（美國普雷西斯公司（Praecis））；AZD 9935（英國阿斯利康公司）；AZD 2171（英國阿斯利康公司）；瓦他拉尼（pINN）（瑞士諾華製藥公司及德國先靈公司（Schering AG））；組織因子途徑抑制劑（美國安翠梅德公司）；哌加他尼（Pinn）（美國吉利德科學公司）；束骨薑黃醇（xanthorrhizol）（韓國延世大學（Yonsei University））；基於基因的VEGF-2疫苗（美國斯克裡普斯診所及研究基金會）；SPV5.2（加拿大薩普泰克公司（Supratek））；SDX 103（美國聖地牙哥的加利福尼亞大學（University of California））；PX 478（美國派克斯公司（ProlX））；轉移抑制素（美國安翠梅德公司，現稱為CASI製藥）；肌鈣蛋白I（美國哈佛大學（Harvard University））；SU 6668（美國蘇根公司（SUGEN），現稱為輝瑞製藥公司（Pfizer, Inc.））；OXI 4503（美國奧克斯吉尼公司（OXiGENE））；鄰胍（美國維度製藥公司（Dimensional Pharmaceuticals））；莫托普胺C（motuporamine C）（加拿大不列顛哥倫比亞大學（British Columbia University））；CDP 791（英國細胞科技集團（Celltech Group））；阿替莫德（pINN）（英國葛蘭素史克公司（GlaxoSmithKline））；E 7820（日本衛材株式會社（Eisai））；CYC 381（美國哈佛大學）；AE 941（加拿大依特納公司）；血管發生疫苗（美國安翠梅德公司，現稱為CASI製藥）；尿激酶纖溶酶原激活劑抑制劑（美國丹德里昂公司）；奧穀法奈（oglufanide）（pINN）（美國麥爾墨特公司（Melmotte））；HIF-1α抑制劑（英國新諾瓦公司（Xenova））；CEP 5214（美國瑟法隆公司）；BAY RES 2622（德國拜耳公司（Bayer））；安吉西丁（美國英可因公司）；A6（美國奧創公司（Angstrom））；KR 31372（韓國的韓國化學技術研究所（Korea Research Institute of Chemical Technology））；GW 2286（英國葛蘭素史克公司）；EHT 0101（法國埃克森海特公司（ExonHit））；CP 868596（美國輝瑞公司）；CP 564959（美國OSI公司）；CP 547632（美國輝瑞公司）；786034（英國葛蘭素史克公司）；KRN 633（日本麒麟啤酒株式會社（Kirin Brewery））；眼內2-甲氧基雌二醇藥物遞送系統（美國安翠梅德公司）；安吉尼克（anginex）（荷蘭馬斯特里赫特大學（Maastricht University）及美國明尼蘇達大學（Minnesota University））；ABT 510（美國雅培公司）；AAL 993（瑞士諾華製藥公司）；VEGI（美國普若技術公司（ProteomTech））；腫瘤壞死因子-α抑制劑（美國國立衰老研究所（National Institute on Aging））；SU 11248（美國輝瑞公司及美國蘇根公司）；ABT 518（美國雅培公司）；YH16（中國煙台榮昌公司（Yantai Rongchang））；S-3APG（美國波士頓兒童醫院及美國安翠梅德公司）；MAb, KDR（美國英殖株系統公司（ImClone Systems））；MAb α5β1（美國蛋白質設計公司（Protein Design））；KDR激酶抑制劑（英國細胞科技集團及美國強生公司）；GFB 116（美國南佛羅里達大學（South Florida University）及美國耶魯大學（Yale University））；CS 706（日本三協株式會社（Sankyo））；康普瑞汀（combretastatin）A4前驅藥（美國亞利桑那州立大學（Arizona State University））；軟骨素酶AC（chondroitinase AC）（加拿大阿卑斯公司（IBEX））；BAY RES 2690（德國拜耳公司）；AGM 1470（美國哈佛大學、日本武田株式會社及美國TAP公司）；AG 13925（美國阿古倫公司（Agouron））；四硫鉬酸鹽（美國密西根大學（University of Michigan））；GCS 100（美國韋恩州立大學（Wayne State University））；CV 247（英國常春藤醫療公司（Ivy Medical））；CKD 732（韓國鐘根堂公司（Chong Kun Dang））；血管內皮生長因子MAb（英國新諾瓦公司）；伊索拉定（irsogladine）（INN）（日本新藥株式會社（Nippon Shinyaku））；RG 13577（法國安萬特公司）；WX 360（德國威萊克斯公司（Wilex））；角鯊胺（pINN）（美國吉納諾公司（Genaera））；RPI 4610（美國瑟納公司（Sirna））；癌症療法（澳大利亞馬力諾瓦公司（Marinova））；類肝素酶抑制劑（以色列洞見公司（InSight））；KL 3106（韓國科隆公司（Kolon））；及厚樸酚（美國埃默里大學（Emory University））；ZK CDK（德國先靈公司）；ZK Angio（德國先靈公司）；ZK 229561（瑞士諾華製藥公司及德國先靈公司）；XMP 300（美國逍馬公司）；VGA 1102（日本大正株式會社（Taisho））；VEGF受體調節劑（美國藥典公司（Pharmacopeia））；VE-鈣粘蛋白-2拮抗劑（美國英殖株系統公司）；伐索他汀（Vasostatin）（美國國立衛生研究院（National Institutes of Health））；Flk-1疫苗（美國英殖株系統公司）；TZ 93（日本津村株式會社）；腫瘤抑素（美國貝斯以色列醫院（Beth Israel Hospital））；截短型可溶FLT 1（血管內皮生長因子受體1）（美國默克公司（Merck & Co））；Tie-2配位基（美國再生元公司）；及血小板反應蛋白1抑制劑（美國阿列格尼健康、教育及研究基金會（Allegheny Health, Education and Research Foundation））。Other anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, now CASI Pharmaceuticals, USA); TLC ELL-12 (Elon, Ireland); anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands); DAC: antiangiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko Kogyo Co., Ltd., Japan); Hakko); SU-0879 (Pfizer); CGP-79787 (Novartis Pharmaceuticals, Switzerland, EP 970070); ARGENT technology (Ariad); YIGSR-Stealth (Johnson &Johnson); Fibrinogen-E fragment (Biotech); angiogenesis inhibitor (Trigen); TBC-1635 (Encysive Pharmaceuticals, USA Pharmaceuticals); SC-236 (Pfizer); ABT-567 (Abbott); Metastatin (Antrimed); Angiogenesis inhibitor (Tripep); Maspin (Sosei); 2-Methoxyestradiol (Oncology Sciences Corporation); ER-68203-00 (IVAX); Fluazifop (Lane Labs); Tz-93 (Tsumura); TAN-1120 (Takeda); FR-111142 (Fujisawa, JP 02233610); platelet factor 4 (RepliGen, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenesis inhibitor (Sugen, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); second-generation MAb α5β3 integrin (Applied Molecular Evolution, USA and MedImmune, USA); gene therapy for retinal diseases (Oxford BioMedica, UK); enzastaurin hydrochloride hydrochloride) (USAN) (Lilly, USA); CEP 7055 (Cerfaron, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitors (Alchemia, Australia); VEGF antagonists (Regeneron, USA); rBPI 21 and BPI-derived antiangiogenic agents (XOMA, USA); PI 88 (Progen, Australia); silengitide (pINN) (Merck, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA) Foundation); Cetuximab (INN) (Aventis, France); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); Angiostatin (Boston Children's Hospital, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor (Antrimed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthorrhizol (Yonsei University, South Korea); gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX 478 (ProlX, USA); metastatin (Antrimed, USA, now known as CASI Pharmaceuticals); sarcosin I (Harvard University, USA); SU 6668 (SUGEN, USA, now known as Pfizer, Inc.); OXI 4503 (OXiGENE, USA); guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); pINN (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Eterna, Canada); angiogenesis vaccine (Antrimed, USA, now known as CASI Pharmaceuticals); urokinase fibrinolytic activator inhibitor (Dendrion, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cerfalon, USA); BAY RES 2622 (Bayer, Germany); Angisidin (Incoin, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); intraocular 2-methoxyestradiol drug delivery system (Antrimed, USA); anginex (Maastricht University, Netherlands and Minnesota University, USA); ABT 510 (Abbott Laboratories, USA); AAL 993 (Novartis Pharmaceuticals, Switzerland); VEGI (ProteomTech, USA); TNF-α inhibitor (National Institute on Aging, USA); SU 11248 (Pfizer, USA and Sugen, USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and Atramed, USA); MAb, KDR (ImClone Systems, USA); MAb α5β1 (Protein Design, USA); KDR kinase inhibitor (Cell Technology Group, UK and Johnson & Johnson, USA); GFB 116 (University of South Florida, USA) University and Yale University; CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, Japan, Takeda Company, and TAP, USA); AG 13925 (Agouron, USA); molybdenum tetrathioate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); vascular endothelial growth factor MAb (Sinovac, UK); irsogladine (INN) (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamide (pINN) (Genaera, USA); RPI 4610 (Sirna, USA); cancer therapy (Marinova, Australia); heparanase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); and magnolol (Emory University, USA); ZK CDK (Schering, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis AG and Schering AG, Switzerland); XMP 300 (Xiao Ma Corporation, USA); VGA 1102 (Taisho Corporation, Japan); VEGF receptor modulator (Pharmacopeia, USA); VE-calcineurin-2 antagonist (British System Corporation, USA); vasostatin (National Institutes of Health, USA); Flk-1 vaccine (British System Corporation, USA); TZ 93 (Tsumura Co., Ltd., Japan); oncostatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co., USA) Co)); Tie-2 ligand (Regeneron Corporation); and thrombospondin-1 inhibitor (Allegheny Health, Education and Research Foundation).

自體吞噬抑制劑包括但不限於氯喹、3-甲基腺嘌呤、羥氯喹（Plaquenil™）、巴弗洛黴素A1（bafilomycin A1）、5-胺基-4-咪唑甲醯胺核糖核苷（AICAR）、岡田酸、抑制2A型或1型蛋白磷酸酶的自體吞噬抑制性海藻毒素、cAMP類似物以及升高cAMP水平的藥物例如腺苷、LY204002、N6-巰嘌呤核糖核苷及長春鹼。另外，亦可以使用抑制蛋白質表現的反義或siRNA，該等蛋白質包括但不限於ATG5（其參與自體吞噬）。Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide ribonucleoside (AICAR), Okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels such as adenosine, LY204002, N6-hexadecene ribonucleoside, and vinblastine. In addition, antisense or siRNAs that inhibit the expression of proteins, including but not limited to ATG5 (which is involved in autophagy), can also be used.

可以用於治療癌症並且可以與本發明的一種或多種化合物組合使用的其他藥學活性化合物/藥劑包括：紅血球生成素α；阿法達貝泊汀（darbepoetin alfa）；帕尼單抗（panitumumab）；培非格司亭（pegfilgrastim）；帕利夫明（palifermin）；非格司亭（filgrastim）；地諾單抗（denosumab）；安西司亭（ancestim）；AMG 102；AMG 176；AMG 386；AMG 479；AMG 655；AMG 745；AMG 951；及AMG 706，或其藥學上可接受的鹽。Other pharmaceutically active compounds/agents that can be used to treat cancer and can be used in combination with one or more compounds of the present invention include: erythropoietin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG 102; AMG 176; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; and AMG 706, or pharmaceutically acceptable salts thereof.

在某些實施方式中，將本文所提供的組成物與化學治療劑聯合施用。適合的化學治療劑可以包括天然產物，例如長春花生物鹼（例如，長春鹼、長春新鹼及長春瑞濱）、紫杉酚、表鬼臼毒素（epidipodophyllotoxin）（例如，依託泊苷及替尼泊苷）、抗生素（例如，更生黴素（放線菌素D）、道諾黴素、多柔比星及伊達比星）、蒽環類抗生素、米托蒽醌、博來黴素、普卡黴素（光輝黴素）、絲裂黴素、酶（例如，L-天冬醯胺酶，其系統性地代謝L-天冬醯胺並剝奪不具有合成自身天冬醯胺的能力的細胞）、抗血小板劑、抗增殖/抗有絲分裂烷基化劑（例如氮芥，例如，二氯甲基二乙胺、環磷醯胺及類似物、美法侖及苯丁酸氮芥）、乙烯亞胺及甲基蜜胺（例如，六甲基蜜胺（hexaamethylmelaamine）及噻替派）、CDK抑制劑（例如，塞利西利（seliciclib）、UCN-01、P1446A-05、PD-0332991、迪那西利（dinaciclib）、P27-00、AT-7519、RGB286638及SCH727965）、烷基磺酸酯（例如，白消安）、亞硝基脲（例如，卡莫司汀（BCNU）及類似物及鏈脲黴素）、三氮烯-達卡巴𠯤（trazenes-dacarbazinine）（DTIC）、抗增殖/抗有絲分裂抗代謝藥例如葉酸類似物（例如，胺甲喋呤）、嘧啶類似物（例如，氟尿嘧啶、氟尿苷及阿糖胞苷）、嘌呤類似物及相關抑制劑（例如，巰嘌呤、硫鳥嘌呤、噴司他丁及2-氯去氧腺苷）、芳香酶抑制劑（例如，阿那曲唑、依西美坦及來曲唑）及鉑配位錯合物（例如，順鉑及卡鉑）、丙卡巴肼、羥基脲、米托坦、胺魯米特、組蛋白脫乙醯酶（HDAC）抑制劑（例如，曲古抑菌素、丁酸鈉、阿匹西坦（apicidan）、辛二醯苯胺異羥肟酸（hydroamic acid）、伏立諾他（vorinostat）、LBH 589、羅米地辛（romidepsin）、ACY-1215及帕比司他（panobinostat））、mTor抑制劑（例如，替西羅莫司、依維莫司、地磷莫司（ridaforolimus）及西羅莫司）、KSP（Eg5）抑制劑（例如，Array 520）、DNA結合劑（例如，紮利普斯（Zalypsis））、PI3Kδ抑制劑（例如，GS-1101及TGR-1202）、PI3Kδ及γ抑制劑（例如，CAL-130）、多激酶抑制劑（例如，TG02及索拉非尼）、激素（例如，雌激素）及激素激動劑例如黃體化激素釋放激素（LHRH）激動劑（例如，戈舍瑞林、亮丙瑞林及曲普瑞林）、BAFF中和性抗體（例如，LY2127399）、IKK抑制劑、p38MAPK抑制劑、抗IL-6（例如，CNTO328）、端粒酶抑制劑（例如，GRN 163L）、極光激酶抑制劑（例如，MLN8237）、細胞表面單株抗體（例如，抗CD38（HUMAX-CD38）、抗CS1（例如，埃羅妥珠單抗（elotuzumab））、HSP90抑制劑（例如，17 AAG及KOS 953）、P13K/Akt抑制劑（例如，哌立福辛（perifosine））、Akt抑制劑（例如，GSK-2141795）、PKC抑制劑（例如，恩紮妥林）、FTI（例如，Zarnestra™）、抗CD138（例如，BT062）、Torc1/2特異性激酶抑制劑（例如，INK128）、激酶抑制劑（例如，GS-1101）、ER/UPR靶向劑（例如，MKC-3946）、cFMS抑制劑（例如，ARRY-382）、JAK1/2抑制劑（例如，CYT387）、PARP抑制劑（例如，奧拉帕尼及維利帕尼（veliparib）（ABT-888））、BCL-2拮抗劑。其他化學治療劑可以包括二氯甲基二乙胺、喜樹鹼、異環磷醯胺、他莫昔芬、雷洛昔芬、吉西他濱、諾維本、索拉非尼或前述項的任何類似物或衍生物變體。In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent. Suitable chemotherapeutic agents may include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), taxol, epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunomycin, doxorubicin, and idarubicin), anthracycline antibiotics, mitoxantrone, bleomycin, plicamycin (glossycin), mitomycin, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and deprive cells of the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative/antimitotic alkylating agents (e.g., nitrogen mustards, e.g., dichloromethyldiethylamine, cyclophosphamide and analogs, melphalan and chlorambucil), ethyleneimines and methylmelamines (e.g., hexamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-03 32991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs and streptozotocin), trazenes-dacarbazinine (DTIC), antiproliferative/antimitotic antimetabolic drugs such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., purine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cis-platinum and carboplatin), procarbazine, hydroxyurea, mitotane, amiodarone, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, hydroamic acid, acid), vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zalypsis), PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3Kδ and γ inhibitors (e.g., CAL-130), multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogens) and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K/Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torc1/2 specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), ER/UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1/2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), BCL-2 antagonists. Other chemotherapeutic agents may include dichloromethane, camptothecin, isocyclic phosphamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analog or derivative variant of the foregoing.

本發明的化合物亦可以與放射療法、激素療法、手術及免疫療法組合使用，該等療法係熟習此項技術者所熟知的。The compounds of the present invention can also be used in combination with radiation therapy, hormone therapy, surgery and immunotherapy, which are well known to those skilled in the art.

在某些實施方式中，將本文所提供的藥物組成物與類固醇聯合施用。適合的類固醇可以包括但不限於21-乙醯氧基孕烯醇酮、阿氯米松、阿爾孕酮、安西奈德、倍氯米松（beclomethasone）、倍他米松、布地奈德、氯普賴鬆（chloroprednisone）、氯倍他索（clobetasol）、氯可托龍、氯潑尼醇、皮質酮、可的松、可的伐唑、地夫可特、地奈德、去羥米松、地塞米松、二氟拉松（diflorasone）、二氟可龍（diflucortolone）、二氟孕甾丁酯（difuprednate）、甘草次酸、氟紮可特、氟氯奈德（flucloronide）、氟米松（flumethasone）、氟尼縮松、氟輕鬆（fluocinolone acetonide）、醋酸氟輕鬆、氟考丁酯（fluocortin butyl）、氟可龍、氟米龍（fluorometholone）、醋酸甲氟龍（fluperolone acetate）、醋酸氟潑尼定（fluprednidene acetate）、氟潑尼龍（fluprednisolone）、氟氫縮松（flurandrenolide）、丙酸氟替卡松、福莫可他（formocortal）、氯氟舒松（halcinonide）、丙酸鹵倍他索（halobetasol propionate）、鹵米松（halometasone）、氫化可的松（hydrocortisone）、依碳酸氯替潑諾（loteprednol etabonate）、馬潑尼酮、甲羥松、甲普賴鬆、甲潑尼龍（methylprednisolone）、糠酸莫米松（mometasone furoate）、帕拉米松、潑尼卡酯、普賴蘇穠（prednisolone）、普賴蘇穠25-二乙胺基乙酸酯、普賴蘇穠磷酸鈉、普賴鬆（prednisone）、普賴蘇穠戊酸酯（prednival）、潑尼立定（prednylidene）、利美索龍、替可的松（tixocortol）、曲安西龍（triamcinolone）、曲安奈德（triamcinolone acetonide）、苯曲安奈德（triamcinolone benetonide）、己曲安奈德（triamcinolone hexacetonide）及其鹽及/或衍生物。在一個特定實施方式中，本發明的化合物亦可以與治療噁心的其他藥學活性藥劑組合使用。可以用於治療噁心的藥劑的實例包括：屈大麻酚（dronabinol）；格拉司瓊（granisetron）；甲氧氯普胺（metoclopramide）；昂丹司瓊（ondansetron）；及丙氯拉𠯤（prochlorperazine）；或其藥學上可接受的鹽。In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids may include, but are not limited to, 21-acetyloxypregnenolone, alclomethasone, algestrone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednisolone, corticosterone, cortisone, cortivazole, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, glycyrrhetinic acid, fluzacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocortin acetate, fluocortin butyl, fluocortin acetonide, fluocortolone ... butyl), fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, maprednione, methylprednisolone, mometasone furoate The invention relates to nausea, vomitories, nausea, vomitories, vomitories 25-diethylamino acetate, vomitories sodium phosphate, vomitories, vomitories valerate ... Examples of drugs that may be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

本發明的化合物亦可以與破壞或抑制RAS-RAF-ERK或PI3K-AKT-TOR信號傳導途徑的其他藥學活性化合物組合使用。在其他此類組合中，其他藥學活性化合物係PD-1及PD-L1拮抗劑。本揭露的化合物或藥物組成物亦可以與一定量的一種或多種選自以下的物質組合使用：EGFR抑制劑、MEK抑制劑、PI3K抑制劑、AKT抑制劑、TOR抑制劑、Mcl-1抑制劑、BCL-2抑制劑、SHP2抑制劑、蛋白酶體抑制劑及免疫療法，包括單株抗體、免疫調節性醯亞胺（IMiD）、抗PD-1、抗PDL-1、抗CTLA4、抗LAG1及抗OX40劑、GITR激動劑、CAR-T細胞及BiTE。The compounds of the present invention can also be used in combination with other pharmaceutically active compounds that disrupt or inhibit the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway. In other such combinations, the other pharmaceutically active compounds are PD-1 and PD-L1 antagonists. The compounds or pharmaceutical compositions disclosed herein may also be used in combination with a certain amount of one or more substances selected from the following: EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors and immunotherapy, including monoclonal antibodies, immunomodulatory amides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1 and anti-OX40 agents, GITR agonists, CAR-T cells and BiTEs.

EGFR抑制劑包括但不限於小分子拮抗劑、抗體抑制劑或特定反義核苷酸或siRNA。有用的EGFR抗體抑制劑包括西妥昔單抗（cetuximab）（愛必妥（Erbitux））、帕尼單抗（panitumumab）（維克替比（Vectibix））、紮魯木單抗（zalutumumab）、尼妥珠單抗（nimotuzumab）及馬妥珠單抗（matuzumab）。EGFR的小分子拮抗劑包括吉非替尼（gefitinib）、厄洛替尼（erlotinib）（特羅凱（Tarceva））及最近的拉帕替尼（lapatinib）（泰克博（TykerB））。參見例如，Yan L等人,Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development [腫瘤治療抗體研發中的遺傳藥理學及藥物基因組學], BioTechniques [生物技術] 2005; 39(4): 565-8，及Paez J G等人,EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy [肺癌中的EGFR突變與對吉非替尼療法的臨床反應的關聯], Science [科學] 2004; 304(5676): 1497-500。EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful EGFR antibody inhibitors include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently, lapatinib (TykerB). See, e.g., Yan L et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development , BioTechniques 2005; 39(4): 565-8, and Paez JG et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004; 304(5676): 1497-500.

小分子EGFR抑制劑的非限制性實例包括以下專利公開案中描述的任何EGFR抑制劑、以及所述EGFR抑制劑的所有藥學上可接受的鹽及溶劑化物：歐洲專利申請案EP 520722，1992年12月30日公開；歐洲專利申請案EP 566226，1993年10月20日公開；PCT國際公開案WO 96/33980，1996年10月31日公開；美國專利號5,747,498，1998年5月5日授權；PCT國際公開案WO 96/30347，1996年10月3日公開；歐洲專利申請案EP 787772，1997年8月6日公開；PCT國際公開案WO 97/30034，1997年8月21日公開；PCT國際公開案WO 97/30044，1997年8月21日公開；PCT國際公開案WO 97/38994，1997年10月23日公開；PCT國際公開案WO 97/49688，1997年12月31日公開；歐洲專利申請案EP 837063，1998年4月22日公開；PCT國際公開案WO 98/02434，1998年1月22日公開；PCT國際公開案WO 97/38983，1997年10月23日公開；PCT國際公開案WO 95/19774，1995年7月27日公開；PCT國際公開案WO 95/19970，1995年7月27日公開；PCT國際公開案WO 97/13771，1997年4月17日公開；PCT國際公開案WO 98/02437，1998年1月22日公開；PCT國際公開案WO 98/02438，1998年1月22日公開；PCT國際公開案WO 97/32881，1997年9月12日公開；德國申請案DE 19629652，1998年1月29日公開；PCT國際公開案WO 98/33798，1998年8月6日公開；PCT國際公開案WO 97/32880，1997年9月12日公開；PCT國際公開案WO 97/32880，1997年9月12日公開；歐洲專利申請案EP 682027，1995年11月15日公開；PCT國際公開案WO 97/02266，197年1月23日公開；PCT國際公開案WO 97/27199，1997年7月31日公開；PCT國際公開案WO 98/07726，1998年2月26日公開；PCT國際公開案WO 97/34895，1997年9月25日公開；PCT國際公開案WO 96/31510’，1996年10月10日公開；PCT國際公開案WO 98/14449，1998年4月9日公開；PCT國際公開案WO 98/14450，1998年4月9日公開；PCT國際公開案WO 98/14451，1998年4月9日公開；PCT國際公開案WO 95/09847，1995年4月13日公開；PCT國際公開案WO 97/19065，1997年5月29日公開；PCT國際公開案WO 98/17662，1998年4月30日公開；美國專利號5,789,427，1998年8月4日授權；美國專利號5,650,415，1997年7月22日授權；美國專利號5,656,643，1997年8月12日授權；PCT國際公開案WO 99/35146，1999年7月15日公開；PCT國際公開案WO 99/35132，1999年7月15日公開；PCT國際公開案WO 99/07701，1999年2月18日公開；及PCT國際公開案WO 92/20642，1992年11月26日公開。小分子EGFR抑制劑的其他非限制性實例包括描述於Traxler, P., 1998, Exp. Opin. Ther. Patents [治療術專利專家評述] 8(12):1599-1625中的任何EGFR抑制劑。Non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in the following patent publications, and all pharmaceutically acceptable salts and solvates of the EGFR inhibitors: European Patent Application EP 520722, published on December 30, 1992; European Patent Application EP 566226, published on October 20, 1993; PCT International Publication WO 96/33980, published on October 31, 1996; U.S. Patent No. 5,747,498, issued on May 5, 1998; PCT International Publication WO 96/30347, published on October 3, 1996; European Patent Application EP 787772, published on August 6, 1997; PCT International Publication No. WO 97/30034, published on August 21, 1997; PCT International Publication No. WO 97/30044, published on August 21, 1997; PCT International Publication No. WO 97/38994, published on October 23, 1997; PCT International Publication No. WO 97/49688, published on December 31, 1997; European Patent Application No. EP 837063, published on April 22, 1998; PCT International Publication No. WO 98/02434, published on January 22, 1998; PCT International Publication No. WO 97/38983, published on October 23, 1997; PCT International Publication No. WO 95/19774, published on July 27, 1995; PCT International Publication No. WO 95/19970, published on July 27, 1995; PCT International Publication No. WO 97/13771, published on April 17, 1997; PCT International Publication No. WO 98/02437, published on January 22, 1998; PCT International Publication No. WO 98/02438, published on January 22, 1998; PCT International Publication No. WO 97/32881, published on September 12, 1997; German Application No. DE 19629652, published on January 29, 1998; PCT International Publication WO 98/33798, published on August 6, 1998; PCT International Publication WO 97/32880, published on September 12, 1997; PCT International Publication WO 97/32880, published on September 12, 1997; European Patent Application EP 682027, published on November 15, 1995; PCT International Publication WO 97/02266, published on January 23, 1997; PCT International Publication WO 97/27199, published on July 31, 1997; PCT International Publication WO 98/07726, published on February 26, 1998; PCT International Publication No. WO 97/34895, published on September 25, 1997; PCT International Publication No. WO 96/31510', published on October 10, 1996; PCT International Publication No. WO 98/14449, published on April 9, 1998; PCT International Publication No. WO 98/14450, published on April 9, 1998; PCT International Publication No. WO 98/14451, published on April 9, 1998; PCT International Publication No. WO 95/09847, published on April 13, 1995; PCT International Publication No. WO 97/19065, published on May 29, 1997; PCT International Publication WO 98/17662, published on April 30, 1998; U.S. Patent No. 5,789,427, issued on August 4, 1998; U.S. Patent No. 5,650,415, issued on July 22, 1997; U.S. Patent No. 5,656,643, issued on August 12, 1997; PCT International Publication WO 99/35146, published on July 15, 1999; PCT International Publication WO 99/35132, published on July 15, 1999; PCT International Publication WO 99/07701, published on February 18, 1999; and PCT International Publication WO 92/20642, published on November 26, 1992. Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in Traxler, P., 1998, Exp. Opin. Ther. Patents [Therapeutic Patent Expert Review] 8(12):1599-1625.

基於抗體的EGFR抑制劑包括可以部分或完全阻斷EGFR被其天然配位基激活的任何抗EGFR抗體或抗體片段。基於抗體的EGFR抑制劑的非限制性實例包括以下文獻中描述的那些：Modjtahedi, H.等人, 1993, Br. J. Cancer [英國癌症雜誌] 67:247-253；Teramoto, T.等人, 1996, Cancer [癌症] 77:639-645；Goldstein等人, 1995, Clin. Cancer Res. [臨床癌症研究] 1:1311-1318；Huang, S. M.等人, 1999, Cancer Res. [癌症研究] 15:59(8):1935-40；及Yang, X.等人, 1999, Cancer Res. [癌症研究] 59:1236-1243。因此，EGFR抑制劑可以是單株抗體Mab E7.6.3（Yang, 1999，同上）、或Mab C225（ATCC登錄號HB-8508）、或具有其結合特異性的抗體或抗體片段。Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block activation of EGFR by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H. et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T. et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318; Huang, S. M. et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X. et al., 1999, Cancer Res. 59:1236-1243. Therefore, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

本發明的KRAS^G12C 抑制劑可以與MEK抑制劑組合使用。可以在本發明的組合中使用的特定的MEK抑制劑包括PD-325901、曲美替尼、匹馬塞替尼、MEK162[也稱為比尼替尼]、TAK-733、GDC-0973及AZD8330。可以在本發明的組合中與KRAS^G12C 抑制劑一起使用的特定MEK抑制劑係曲美替尼（商品名：Mekinist^® ，可購自諾華製藥公司（Novartis Pharmaceuticals Corp.））。另一種特定的MEK抑制劑係N-(((2R)-2,3-二羥丙基)氧基)-3,4-二氟-2-((2-氟-4-碘苯基)胺基)苯甲醯胺，也稱為AMG 1009089、1009089或PD-325901。可用於本發明組合的另一種特定的MEK抑制劑包括考比替尼（cobimetinib）。MEK抑制劑包括但不限於CI-1040、AZD6244、PD318088、PD98059、PD334581、RDEA119、ARRY-142886及ARRY-438162。The KRAS ^G12C inhibitors of the present invention can be used in combination with a MEK inhibitor. Specific MEK inhibitors that can be used in the combination of the present invention include PD-325901, trametinib, pimacetinib, MEK162 [also known as binitinib], TAK-733, GDC-0973, and AZD8330. A specific MEK inhibitor that can be used with a KRAS ^G12C inhibitor in the combination of the present invention is trametinib (trade name: Mekinist ^® , available from Novartis Pharmaceuticals Corp.). Another specific MEK inhibitor is N-(((2R)-2,3-dihydroxypropyl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide, also known as AMG 1009089, 1009089 or PD-325901. Another specific MEK inhibitor that can be used in the combination of the present invention includes cobimetinib. MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886 and ARRY-438162.

PI3K抑制劑包括但不限於渥曼青黴素、WO 06/044453中描述的17-羥基渥曼青黴素類似物、4-[2-(1H-吲唑-4-基)-6-[[4-(甲磺醯基)哌𠯤-1-基]甲基]噻吩并[3,2-d]嘧啶-4-基]嗎啉（亦稱為GDC 0941，並且描述於PCT公開案號WO 09/036,082及WO 09/055,730中）、2-甲基-2-[4-[3-甲基-2-側氧基-8-(喹啉-3-基)-2,3-二氫咪唑并[4,5-c]喹啉-1-基]苯基]丙腈（亦稱為BEZ 235或NVP-BEZ 235，並且描述於PCT公開案號WO 06/122806中）、(S)-1-(4-((2-(2-胺基嘧啶-5-基)-7-甲基-4-嗎啉代噻吩并[3,2-d]嘧啶-6-基)甲基)哌𠯤-1-基)-2-羥基丙-1-酮（描述於PCT公開案號WO 2008/070740中）、LY294002（2-(4-嗎啉基)-8-苯基-4H-1-苯并哌喃-4-酮，可從艾克松醫學化學公司（Axon Medchem)獲得）、PI 103鹽酸鹽（3-[4-(4-嗎啉基吡啶并-[3’,2’:4,5]呋喃并[3,2-d]嘧啶-2-基]苯酚鹽酸鹽，可從艾克松醫學化學公司獲得）、PIK 75（N’-[(1E)-(6-溴代咪唑并[1,2-a]吡啶-3-基)亞甲基]-N,2-二甲基-5-硝基苯磺醯基-醯肼鹽酸鹽，可從艾克松醫學化學公司獲得）、PIK 90（N-(7,8-二甲氧基-2,3-二氫-咪唑并[1,2-c]喹唑啉-5-基)-煙醯胺，可從艾克松醫學化學公司獲得）、GDC-0941二甲磺酸鹽（2-(1H-吲唑-4-基)-6-(4-甲烷磺醯基-哌𠯤-1-基甲基)-4-嗎啉-4-基-噻吩并[3,2-d]嘧啶二甲磺酸鹽，可從艾克松醫學化學公司獲得）、AS-252424（5-[1-[5-(4-氟-2-羥基-苯基)-呋喃-2-基]-甲-(Z)-亞基]-四氫噻唑-2,4-二酮，可從艾克松醫學化學公司獲得）以及TGX-221（7-甲基-2-(4-嗎啉基)-9-[1-(苯基胺基)乙基]-4H-吡啶并-[1,2-a]嘧啶-4-酮，可從艾克松醫學化學公司獲得）、XL-765及XL-147。其他PI3K抑制劑包括去甲氧基綠膠黴素（demethoxyviridin）、哌立福辛、CAL101、PX-866、BEZ235、SF1126、INK1117、IPI-145、BKM120、XL147、XL765、帕羅米德529（Palomid 529）、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、PI-103、GNE-477、CUDC-907及AEZS-136。PI3K inhibitors include, but are not limited to, wortmannin, 17-hydroxy wortmannin analogs described in WO 06/044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperidin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036,082 and WO 09/055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06/122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)-2-hydroxypropan-1-one (described in PCT Publication No. WO 2008/070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Exon Medical Chemicals), PIK 75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfonyl-hydrazine hydrochloride, available from Exon Medical Chemicals), PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide, available from Exxon Medical Chemicals), GDC-0941 dimethanesulfonate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-oxolin-4-yl-thieno[3,2-d]pyrimidine dimethanesulfonate, available from Exxon Medical Chemicals), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-tetrahydrothiazole-2,4-dione, available from Exxon Medical Chemicals Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomide 529, and XL-147. 529), GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907 and AEZS-136.

AKT抑制劑包括但不限於Akt-1-1（抑制Akt1）（Barnett等人（2005）Biochem. J. [生物化學雜誌], 385（Pt. 2）, 399-408）；Akt-1-1,2（抑制Ak1及2）（Barnett等人（2005）Biochem. J. [生物化學雜誌] 385 (Pt. 2), 399-408）；API-59CJ-Ome（例如，Jin等人（2004）Br. J. Cancer [英國癌症雜誌] 91, 1808-12）；1-H-咪唑并[4,5-c]吡啶基化合物（例如，WO 05011700）；吲哚-3-甲醇（carbinol）及其衍生物（例如，美國專利號6,656,963；Sarkar及Li (2004)J Nutr. [營養學雜誌]134(12增刊), 3493S-3498S）；哌立福辛（例如，干擾Akt膜定位；Dasmahapatra等人 (2004)Clin. Cancer Res. [臨床癌症研究] 10(15), 5242-52, 2004）；磷脂醯肌醇醚脂質類似物（例如，Gills及Dennis（2004）Expert. Opin. Investig. Drugs [研究藥物專家評論]13, 787-97）；及曲西立濱（TCN或API-2或NCI識別符：NSC 154020；Yang等人 (2004)Cancer Res. [癌症研究] 64, 4394-9）。AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J. , 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al. (2005) Biochem. J. , 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer , 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) J Nutr. 134(12 Suppl), 3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64, 4394-9).

TOR抑制劑包括但不限於，AP-23573、CCI-779、依維莫司、RAD-001、雷帕黴素、替西羅莫司、ATP競爭性TORC1/TORC2抑制劑，包括PI-103、PP242、PP30及托林1（Torin 1）。其他TOR抑制劑包括FKBP12增強劑；雷帕黴素及其衍生物，包括：CCI-779（替西羅莫司）、RAD001（依維莫司；WO 9409010）及AP23573；雷帕黴素類似物（rapalog），例如如WO 98/02441及WO 01/14387中所揭露，例如AP23573、AP23464或AP23841；40-(2-羥乙基)雷帕黴素、40-[3-羥基(羥甲基)甲基丙酸酯]-雷帕黴素（亦稱為CC1779）、40-表-(四唑基)-雷帕黴素（亦稱為ABT578）、32-去氧雷帕黴素、16-戊炔氧基-32(S)-二氫雷帕黴素及WO 05005434中揭露的其他衍生物；以下專利中揭露的衍生物：美國專利號5,258,389、WO 94/090101、WO 92/05179、美國專利號5,118,677、美國專利號5,118,678、美國專利號5,100,883、美國專利號5,151,413、美國專利號5,120,842、WO 93/111130、WO 94/02136、WO 94/02485、WO 95/14023、WO 94/02136、WO 95/16691、WO 96/41807、WO 96/41807及美國專利號5,256,790；含磷雷帕黴素衍生物（例如，WO 05016252）；4H-1-苯并哌喃-4-酮衍生物（例如，美國臨時申請案號60/528,340）。TOR inhibitors include, but are not limited to, AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, and Torin 1. Other TOR inhibitors include FKBP12 enhancers; rapamycin and its derivatives, including: CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010) and AP23573; rapamycin analogs (rapalogs), such as WO 98/02441 and WO 01/14387, such as AP23573, AP23464 or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapamycin (also known as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxyrapamycin, 16-pentynyloxy-32(S)-dihydrorapamycin and other derivatives disclosed in WO 05005434; derivatives disclosed in the following patents: U.S. Patent No. 5,258,389, WO 94/090101, WO 92/05179, U.S. Patent No. 5,118,677, U.S. Patent No. 5,118,678, U.S. Patent No. 5,100,883, U.S. Patent No. 5,151,413, U.S. Patent No. 5,120,842, WO 93/111130, WO 94/02136, WO 94/02485, WO 95/14023, WO 94/02136, WO 95/16691, WO 96/41807, WO 96/41807 and U.S. Patent No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Application No. 60/528,340).

MCl-1抑制劑包括但不限於AMG-176、MIK665及S63845。髓樣細胞白血病-1（MCL-1）蛋白係B細胞淋巴瘤2（BCL-2）蛋白家族的關鍵抗凋亡成員之一。MCL-1的過表現與腫瘤進展以及不僅針對傳統化學療法亦針對包括BCL-2抑制劑（例如ABT-263）的靶向療法的抗性密切相關。MCl-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma 2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance not only to traditional chemotherapy but also to targeted therapies including BCL-2 inhibitors (e.g., ABT-263).

在本發明中，KRAS^G12C 抑制劑也可以與SHP2抑制劑組合使用。可以在本發明組合中使用的SHP2抑制劑包括但不限於SHP099，以及RMC-4550或RMC-4630（來自加利福尼亞州紅木市（Redwood City, CA）的Revolutions Medicines）。In the present invention, KRAS ^G12C inhibitors can also be used in combination with SHP2 inhibitors. SHP2 inhibitors that can be used in the combination of the present invention include but are not limited to SHP099, and RMC-4550 or RMC-4630 (from Revolutions Medicines in Redwood City, CA).

蛋白酶體抑制劑包括但不限於Kyprolis^® （卡非佐米）、Velcade^® （硼替佐米）及奧普佐米（oprozomib）。Proteasome inhibitors include, but are not limited to, Kyprolis ^® (carfilzomib), Velcade ^® (bortezomib), and oprozomib.

免疫療法包括但不限於抗PD-1劑、抗PDL-1劑、抗CTLA-4劑、抗LAG1劑及抗OX40劑。Immunotherapy includes but is not limited to anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents and anti-OX40 agents.

單株抗體包括但不限於Darzalex^® （達雷木單抗（daratumumab））、Herceptin^® （曲妥珠單抗（trastuzumab））、Avastin^® （貝伐珠單抗（bevacizumab））、Rituxan^® （利妥昔（rituximab））、Lucentis^® （雷珠單抗（ranibizumab））、及Eylea^® （阿柏西普（aflibercept））。Monoclonal antibodies include, but are not limited to, Darzalex ^® (daratumumab), Herceptin ^® (trastuzumab), Avastin ^® (bevacizumab), Rituxan ^® (rituximab), Lucentis ^® (ranibizumab), and Eylea ^® (aflibercept).

免疫調節劑（IMiD）係一類含有醯亞胺基團的免疫調節藥物（調節免疫反應的藥物）。IMiD類包括沙利度胺及其類似物（來那度胺、泊馬利度胺及阿米司特）。Immunomodulatory drugs (IMiDs) are a class of immunomodulatory drugs (drugs that modulate immune responses) that contain an imide group. IMiDs include thalidomide and its analogs (lenalidomide, pomalidomide, and amilast).

包括但不限於抗體的抗PD-1抑制劑包括但不限於派姆單抗（Keytruda^® ）及納武單抗（Opdivo^® ）。示例性抗PD-1抗體及其使用方法描述於以下文獻中：Goldberg等人,Blood [血液] 110(1):186-192 （2007）；Thompson等人,Clin. Cancer Res. [臨床癌症研究] 13(6):1757-1761 （2007）；及Korman等人, 國際申請案號PCT/JP2006/309606（公開案號WO 2006/121168 A1），將其各自藉由引用明確併入本文。包括：Yervoy™（伊匹單抗（ipilimumab））或曲美目單抗（Tremelimumab）（針對CTLA-4）、加利昔單抗（galiximab）（針對B7.1）、BMS-936558（針對PD-1）、MK-3475（針對PD-1）、AMP224（針對B7DC）、BMS-936559（針對B7-H1）、MPDL3280A（針對B7-H1）、MEDI-570（針對ICOS）、AMG557（針對B7H2）、MGA271（針對B7H3）、IMP321（針對LAG-3）、BMS-663513（針對CD137）、PF-05082566（針對CD137）、CDX-1127（針對CD27）、抗OX40（普羅維登斯衛生服務（Providence Health Services））、huMAbOX40L（針對OX40L）、阿塞西普（Atacicept）（針對TACI）、CP-870893（針對CD40）、魯卡木單抗（Lucatumumab）（針對CD40）、達西珠單抗（Dacetuzumab）（針對CD40）、莫羅單抗-CD3（Muromonab-CD3）（針對CD3）、伊匹單抗（針對CTLA-4）。免疫療法亦包括遺傳工程化的T細胞（例如，CAR-T細胞）及雙特異性抗體（例如，BiTE）。Anti-PD-1 inhibitors, including but not limited to antibodies, include but are not limited to pembrolizumab ( ^Keytruda® ) and nivolumab ( ^Opdivo® ). Exemplary anti-PD-1 antibodies and methods of use thereof are described in the following references: Goldberg et al., Blood 110(1):186-192 (2007); Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007); and Korman et al., International Application No. PCT/JP2006/309606 (Publication No. WO 2006/121168 A1), each of which is expressly incorporated herein by reference. Including: Yervoy™ (ipilimumab) or Tremelimumab (targeting CTLA-4), galiximab (targeting B7.1), BMS-936558 (targeting PD-1), MK-3475 (targeting PD-1), AMP224 (targeting B7DC), BMS-936559 (targeting B7-H1), MPDL32 80A (for B7-H1), MEDI-570 (for ICOS), AMG557 (for B7H2), MGA271 (for B7H3), IMP321 (for LAG-3), BMS-663513 (for CD137), PF-05082566 (for CD137), CDX-1127 (for CD27), anti-OX40 (Providence Health Services Health Services), huMAbOX40L (targeting OX40L), Atacicept (targeting TACI), CP-870893 (targeting CD40), Lucatumumab (targeting CD40), Dacetuzumab (targeting CD40), Muromonab-CD3 (targeting CD3), Ipilimumab (targeting CTLA-4). Immunotherapy also includes genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE).

GITR激動劑包括但不限於GITR融合蛋白及抗GITR抗體（例如二價抗GITR抗體），例如美國專利號6,111,090box.c、歐洲專利號：090505B1、美國專利號8,586,023、PCT公開號：WO 2010/003118及2011/090754中所述的GITR融合蛋白，或例如在以下中描述的抗GITR抗體：美國專利號7,025,962、歐洲專利號：1947183B1、美國專利號7,812,135、美國專利號8,388,967、美國專利號8,591,886、歐洲專利號：EP 1866339、PCT公開號：WO 2011/028683、PCT公開號：WO 2013/039954、PCT公開號：WO 2005/007190、PCT公開號：WO 2007/133822、PCT公開號：WO 2005/055808、PCT公開號：WO 99/40196、PCT公開號：WO 2001/03720、PCT公開號：WO 99/20758、PCT公開號：WO 2006/083289、PCT公開號：WO 2005/115451、美國專利號7,618,632及PCT公開號：WO 2011/051726。GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as GITR fusion proteins described in U.S. Patent No. 6,111,090box.c, European Patent No. 090505B1, U.S. Patent No. 8,586,023, PCT Publication Nos. WO 2010/003118 and 2011/090754, or anti-GITR antibodies such as described in U.S. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, European Patent No. EP 1866339, PCT Publication No. WO 2011/028683, PCT Publication No.: WO 2013/039954, PCT Publication No.: WO 2005/007190, PCT Publication No.: WO 2007/133822, PCT Publication No.: WO 2005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.: WO 99/20758, PCT Publication No.: WO 2006/083289, PCT Publication No.: WO 2005/115451, U.S. Patent No. 7,618,632 and PCT Publication No.: WO 2011/051726.

本文所述的化合物可以與本文所揭露的藥劑或其他適合的藥劑組合使用，這取決於所治療的病症。因此，在一些實施方式中，本揭露的一種或多種化合物將與如上所述的其他藥劑共投與。在用於組合療法中時，本文所述的化合物與第二藥劑同時或分開投與。這種組合投與可以包括以相同劑型同時投與兩種藥劑、以單獨劑型同時投與及分開投與。也就是說，本文所述的化合物及上述任何藥劑可以一起配製於相同劑型中並同時投與。可替代地，本揭露的化合物及上述任何藥劑可以同時投與，其中兩種藥劑存在於單獨配製物中。在另一個替代方案中，可以在投與本揭露的化合物後立即投與上述任何藥劑，或反之亦然。在單獨投與方案的一些實施方式中，本揭露的化合物及上述任何藥劑的投與相隔幾分鐘，或相隔幾小時，或相隔幾天。The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the disease being treated. Therefore, in some embodiments, one or more compounds disclosed herein will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. This combination administration can include simultaneous administration of two agents in the same dosage form, simultaneous administration in a separate dosage form, and separate administration. In other words, the compounds described herein and any of the above-mentioned agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the above-mentioned agents can be administered simultaneously, wherein the two agents are present in a separate formulation. In another alternative, any of the above-mentioned agents can be administered immediately after the compounds disclosed herein are administered, or vice versa. In some embodiments of the separate administration regimen, the compounds of the present disclosure and any of the above-described agents are administered a few minutes apart, or a few hours apart, or a few days apart.

由於本發明的一個方面考慮了用可以分開投與的藥學活性化合物的組合治療疾病/病症，本發明進一步關於以套組形式組合單獨的藥物組成物。該套組包含兩種單獨的藥物組成物：本發明的化合物及第二藥物化合物。該套組包含用於容納單獨組成物的容器，例如分開的瓶子或分開的箔袋。容器的其他實例包括注射器、盒及袋。在一些實施方式中，該套組包含單獨組分的使用說明。在較佳的是以不同劑型（例如，口服及非經腸）投與單獨組分時，以不同劑量間隔投與時，或在開方的醫護專業人員需要組合中個別組分的滴定時，套組形式係特別有利的。Since one aspect of the present invention contemplates treating diseases/disorders with combinations of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate drug compositions in a kit form. The kit comprises two separate drug compositions: a compound of the present invention and a second drug compound. The kit comprises a container for holding the separate components, such as a separate bottle or a separate foil bag. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises instructions for use of the separate components. The kit form is particularly advantageous when it is preferred to administer the separate components in different dosage forms (e.g., oral and parenteral), when administering at different dosage intervals, or when the prescribing healthcare professional requires titration of the individual components in the combination.

本文引用的所有專利及其他公開案均藉由引用併入本文。All patents and other publications cited herein are incorporated by reference.

下文所呈現的實例說明本發明的具體實施方式。該等實例係代表性的，無意以任何方式限制申請專利範圍的範圍。本發明的代表性實例 The examples presented below illustrate specific embodiments of the present invention. These examples are representative and are not intended to limit the scope of the patent application in any way. Representative Examples of the Present Invention

以下6-氟-7-(2-氟-6-羥基苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S )-2-甲基-4-(2-丙烯醯基)-1-哌𠯤基)吡啶并[2,3-d ]嘧啶-2(1H)-酮的中間體化合物係本發明的代表性實例，並且不應解釋為限制本發明的範圍。The following intermediate compounds of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-(( 2S )-2-methyl-4-(2-propenyl)-1-piperidinyl)pyrido[2,3- d ]pyrimidin-2(1H)-one are representative examples of the present invention and should not be construed as limiting the scope of the present invention.

2017年5月22日提交的美國臨時專利申請中描述了化合物9及相關中間體的合成。6-氟-7-(2-氟-6-羥基苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S )-2-甲基-4-(2-丙烯醯基)-1-哌𠯤基)吡啶并[2,3-d ]嘧啶-2(1H)-酮使用以下方法製備，其中藉由對掌性層析法分離最終產物的異構物。 The synthesis of compound 9 and related intermediates is described in a U.S. provisional patent application filed on May 22, 2017. 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-(( 2S )-2-methyl-4-(2-propenyl)-1-piperidinyl)pyrido[2,3- d ]pyrimidin-2(1H)-one was prepared using the following method, in which the isomers of the final product were separated by chiral chromatography.

步驟 1 ： 2,6- 二氯 -5- 氟煙醯胺（中間體 S ）。向2,6-二氯-5-氟-菸酸（4.0 g，19.1 mmol，愛斯特科技有限公司（AstaTech Inc.）,布里斯托爾, 賓夕法尼亞州））在二氯甲烷（48 mL）中的混合物中添加草醯氯（2M DCM溶液，11.9 mL，23.8 mmol），隨後添加催化量的DMF（0.05 mL）。將反應物在室溫下攪拌過夜，然後濃縮。將殘餘物溶於1,4-二噁烷（48 mL）中，並冷卻至0℃。藉由注射器緩慢添加氫氧化銨溶液（基於NH3 28.0%-30%，3.6 mL，28.6 mmol）。將所得混合物在0℃下攪拌30 min，然後濃縮。用EtOAc/庚烷的1:1混合物稀釋殘餘物，並攪拌5 min，然後過濾。丟棄過濾的固體，且其餘母液部分濃縮至一半體積並過濾。將過濾的固體用庚烷洗滌並在減壓烘箱（45℃）中乾燥過夜，以提供2,6-二氯-5-氟煙醯胺。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.23 (d,J = 7.9 Hz, 1 H) 8.09 (br s, 1 H) 7.93 (br s, 1 H)。m/z (ESI, + ve 離子): 210.9 (M+H)⁺ 。 Step 1 : 2,6- Dichloro - 5-fluoronicotinamide (Intermediate S ). To a mixture of 2,6-dichloro-5-fluoro-nicotinic acid (4.0 g, 19.1 mmol, AstaTech Inc., Bristol, Pennsylvania) in dichloromethane (48 mL) was added oxalyl chloride (2M DCM solution, 11.9 mL, 23.8 mmol) followed by a catalytic amount of DMF (0.05 mL). The reaction was stirred at room temperature overnight and then concentrated. The residue was dissolved in 1,4-dioxane (48 mL) and cooled to 0 °C. Ammonium hydroxide solution (28.0%-30% based on NH3, 3.6 mL, 28.6 mmol) was slowly added via syringe. The resulting mixture was stirred at 0 °C for 30 min and then concentrated. The residue was diluted with a 1:1 mixture of EtOAc/heptane and stirred for 5 min and then filtered. The filtered solid was discarded and the remaining mother liquor was partially concentrated to half volume and filtered. The filtered solid was washed with heptane and dried in a reduced pressure oven (45 °C) overnight to provide 2,6-dichloro-5-fluoronicotinoamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.23 (d, J = 7.9 Hz, 1 H) 8.09 (br s, 1 H) 7.93 (br s, 1 H). m/z (ESI, +ve ion): 210.9 (M+H) ⁺ .

步驟 2 ： 2,6- 二氯 -5- 氟 -N-((2- 異丙基 -4- 甲基吡啶 -3- 基 ) 胺基甲醯基 ) 煙醯胺。 藉由注射器向冰冷卻的2,6-二氯-5-氟煙醯胺（中間體 S ，5.0 g，23.9 mmol）在THF（20 mL）中的漿液中緩慢添加草醯氯（2M DCM溶液，14.4 mL，28.8 mmol）。將所得混合物在75℃下加熱1h，然後停止加熱，並將反應物濃縮至一半體積。冷卻至0℃後，藉由套管逐滴添加THF（20mL），隨後添加2-異丙基-4-甲基吡啶-3-胺（中間體 R ，3.59 g，23.92 mmoL）的THF（10 mL）溶液。將所得混合物在0℃下攪拌1 h，然後用鹽水及飽和氯化銨水溶液的1:1混合物淬滅。將混合物用EtOAc萃取（3x），將合併的有機層經無水硫酸鈉乾燥並濃縮，提供2,6-二氯-5-氟-N -((2-異丙基-4-甲基吡啶-3-基)胺基甲醯基)煙醯胺。該材料未經進一步純化即用於隨後步驟。m/z (ESI, + ve 離子): 385.1(M+H)⁺ 。 Step 2 : 2,6- dichloro -5- fluoro -N-((2- isopropyl -4- methylpyridin -3- yl ) aminoformyl ) nicotinamide. To an ice-cooled slurry of 2,6-dichloro-5-fluoronicotinamide ( intermediate S , 5.0 g, 23.9 mmol) in THF (20 mL) was slowly added oxalyl chloride (2M DCM solution, 14.4 mL, 28.8 mmol) via syringe. The resulting mixture was heated at 75 °C for 1 h, then the heating was stopped and the reaction was concentrated to half volume. After cooling to 0 °C, THF (20 mL) was added dropwise via cannula, followed by a solution of 2-isopropyl-4-methylpyridin-3-amine ( intermediate R , 3.59 g, 23.92 mmol) in THF (10 mL). The resulting mixture was stirred at 0 °C for 1 h and then quenched with a 1:1 mixture of brine and saturated aqueous ammonium chloride solution. The mixture was extracted with EtOAc (3x), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide 2,6-dichloro-5-fluoro- N -((2-isopropyl-4-methylpyridin-3-yl)aminoformyl)nicotinate. This material was used in the subsequent step without further purification. m/z (ESI, +ve ion): 385.1(M+H) ⁺ .

步驟 3 ： 7- 氯 -6- 氟 -1-(2- 異丙基 -4- 甲基吡啶 -3- 基 ) 吡啶并 [2,3-d] 嘧啶 -2,4(1H,3H)- 二酮。 藉由注射器向冰冷卻的2,6-二氯-5-氟-N -((2-異丙基-4-甲基吡啶-3-基)胺基甲醯基)煙醯胺（9.2 g，24.0 mmol）的THF（40 mL）溶液中緩慢添加KHMDS（1M THF溶液，50.2 mL，50.2 mmol）。除去冰浴，並將所得混合物在室溫下攪拌40 min。用飽和氯化銨水溶液淬滅反應，並用EtOAc萃取（3x）。將合併的有機層經無水硫酸鈉乾燥並濃縮。將殘餘物藉由矽膠層析法純化（溶離液：0-50% 3:1 EtOAc-EtOH/庚烷），提供7-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶基[2,3-d ]嘧啶-2,4(1H,3H)-二酮。¹ H NMR (400 MHz, DMSO-d₆ ) δ ppm 12.27 (br s, 1H), 8.48-8.55 (m, 2 H), 7.29 (d,J = 4.8 Hz, 1 H), 2.87 (quin,J = 6.6 Hz, 1 H), 1.99-2.06 (m, 3 H), 1.09 (d,J = 6.6 Hz, 3 H), 1.01 (d,J = 6.6 Hz, 3 H)。¹⁹ F NMR (376 MHz, DMSO-d₆ ) δ: -126.90 （s, 1 F）。m/z (ESI, + ve 離子): 349.1 (M+H)⁺ 。 Step 3 : 7- Chloro -6- fluoro -1-(2- isopropyl -4- methylpyridin- 3- yl ) pyrido [2,3-d] pyrimidine -2,4(1H,3H) -dione. To an ice-cooled solution of 2,6-dichloro-5-fluoro- N -((2-isopropyl-4-methylpyridin-3-yl)aminoformyl)nicotinate (9.2 g, 24.0 mmol) in THF (40 mL) was slowly added KHMDS (1 M in THF, 50.2 mL, 50.2 mmol) via syringe. The ice bath was removed and the resulting mixture was stirred at room temperature for 40 min. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% 3:1 EtOAc-EtOH/heptane) to provide 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyridinyl[2,3- d ]pyrimidine-2,4(1H,3H)-dione. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.27 (br s, 1H), 8.48-8.55 (m, 2 H), 7.29 (d, J = 4.8 Hz, 1 H), 2.87 (quin, J = 6.6 Hz, 1 H), 1.99-2.06 (m, 3 H), 1.09 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ: -126.90 (s, 1 F). m/z (ESI, + ve ion): 349.1 (M+H) ⁺ .

步驟 4 ： 4,7- 二氯 -6- 氟 -1-(2- 異丙基 -4- 甲基吡啶 -3- 基 ) 吡啶并 [2,3-d ] 嘧啶 -2(1H)- 酮。藉由注射器向7-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d ]嘧啶-2,4(1H,3H)-二酮（4.7 g，13.5 mmol）及DIPEA（3.5 mL，20.2 mmol）在乙腈（20 mL）中的溶液中逐滴添加三氯氧化磷（1.63 mL，17.5 mmol）。將所得混合物在80℃下加熱1h，然後冷卻至室溫並濃縮，提供4,7-二氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d ]嘧啶-2(1H)-酮。該材料未經進一步純化即用於隨後步驟。m/z (ESI, + ve 離子): 367.1 (M+H)⁺ 。 Step 4 : 4,7- Dichloro -6- fluoro -1- (2- isopropyl - 4- methylpyridin - 3- yl ) pyrido [2,3- d ] pyrimidin -2 (1H) -one. To a solution of 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidine-2,4(1H,3H)-dione (4.7 g, 13.5 mmol) and DIPEA (3.5 mL, 20.2 mmol) in acetonitrile (20 mL) was added phosphorus oxychloride (1.63 mL, 17.5 mmol) dropwise via syringe. The resulting mixture was heated at 80 °C for 1 h, then cooled to room temperature and concentrated to provide 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2(1H)-one. This material was used in the subsequent step without further purification. m/z (ESI, +ve ion): 367.1 (M+H) ⁺ .

步驟 5 ： (S )-4-(7- 氯 -6- 氟 -1-(2- 異丙基 -4- 甲基吡啶 -3- 基 )-2- 側氧基 -1,2- 二氫吡啶并 [2,3-d ] 嘧啶 -4- 基 )-3- 甲基哌 𠯤 -1- 甲酸三級丁 基酯。 向冰冷卻的4,7-二氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d ]嘧啶-2(1H)-酮（13.5 mmol）在乙腈（20 mL）中的溶液中添加DIPEA（7.1 mL，40.3 mmol），隨後添加(S )-4-N -Boc-2-甲基哌𠯤（3.23 g，16.1 mmol，Combi-Blocks有限公司（Combi-Blocks, Inc.）, 聖地牙哥市, 加利福尼亞州, 美國）。將所得混合物溫熱至室溫並攪拌1 h，然後用冷的飽和碳酸氫鈉水溶液（200 mL）及EtOAc（300 mL）稀釋。將混合物再攪拌5 min，分離各層，並將水層用更多的EtOAc萃取（1x）。將合併的有機層經無水硫酸鈉乾燥並濃縮。將殘餘物藉由矽膠層析法純化（溶離液：0%-50% EtOAc/庚烷），提供(S )-4-(7-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基)-3-甲基哌𠯤-1-甲酸三級丁 基酯。m/z (ESI, + ve 離子): 531.2 (M+H)⁺ 。 Step 5 : ( S )-4-(7- chloro -6- fluoro -1-(2- isopropyl -4- methylpyridin -3- yl )-2 -oxo -1,2- dihydropyrido [2,3- d ] pyrimidin -4 -yl )-3- methylpiperidin - 1- carboxylic acid tributyl ester. To an ice-cold solution of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2(1H)-one (13.5 mmol) in acetonitrile (20 mL) was added DIPEA (7.1 mL, 40.3 mmol) followed by ( S )-4- N -Boc-2-methylpiperidinium (3.23 g, 16.1 mmol, Combi-Blocks, Inc., San Diego, CA, USA). The resulting mixture was warmed to room temperature and stirred for 1 h, then diluted with cold saturated aqueous sodium bicarbonate solution (200 mL) and EtOAc (300 mL). The mixture was stirred for an additional 5 min, the layers were separated, and the aqueous layer was extracted with more EtOAc (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0%-50% EtOAc/heptane) to provide ( S )-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl)-3-methylpiperidin-1-carboxylic acid tributyl ester. m/z (ESI, +ve ion): 531.2 (M+H) ⁺ .

步驟 6 ： (3S )-4-(6- 氟 -7-(2- 氟 -6- 羥基苯基 )-1-(2- 異丙基 -4- 甲基吡啶 -3- 基 )-2- 側氧基 -1,2- 二氫吡啶并 [2,3-d ] 嘧啶 -4- 基 )-3- 甲基哌 𠯤 -1- 甲酸三級丁 基酯。 將(S )-4-(7-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基)-3-甲基哌𠯤-1-甲酸三級丁 基酯（4.3 g，8.1 mmol），三氟(2-氟-6-羥基苯基)硼酸鉀（中間體 Q ，2.9 g，10.5 mmol），乙酸鉀（3.2 g，32.4 mmol）及與二氯甲烷錯合的[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)（661 mg，0.81 mmol）在1,4-二噁烷（80 mL）中的混合物用氮氣脫氣1 min。添加去氧水（14 mL），並將所得混合物在90℃加熱1 h。使反應物冷卻至室溫，用半飽和碳酸氫鈉水溶液淬滅，並用EtOAc（2x）及DCM（1x）萃取。將合併的有機層經無水硫酸鈉乾燥並濃縮。將殘餘物藉由矽膠層析法純化（溶離液：0-60% 3 : 1 EtOAc-EtOH/庚烷），提供(3S )-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基)-3-甲基哌𠯤-1-甲酸三級丁 基酯。¹ H NMR（400 MHz, DMSO-d₆ ）δ ppm 10.19 （br s, 1 H）, 8.38 （d,J = 5.0 Hz, 1 H）, 8.26 （dd,J = 12.5, 9.2 Hz, 1 H）, 7.23-7.28 （m, 1 H）, 7.18 （d,J = 5.0 Hz, 1 H）, 6.72 （d,J = 8.0 Hz, 1 H）, 6.68 （t,J = 8.9 Hz, 1 H）, 4.77-4.98 （m, 1 H）, 4.24 （br t,J = 14.2 Hz, 1 H）, 3.93-4.08 （m, 1 H）, 3.84 （br d,J =12.9 Hz, 1 H）, 3.52-3.75 （m, 1 H）, 3.07-3.28 （m, 1 H）, 2.62-2.74 （m, 1 H）, 1.86-1.93 （m, 3 H）, 1.43-1.48 （m, 9 H）, 1.35 （dd,J = 10.8, 6.8 Hz, 3 H）, 1.26-1.32 （m, 1 H）, 1.07 （dd,J = 6.6, 1.7 Hz, 3 H）, 0.93 （dd,J = 6.6, 2.1 Hz, 3 H）。¹⁹ F NMR (376 MHz, DMSO-d₆ ) δ: -115.65 (s, 1 F), -128.62 (s, 1 F)。m/z (ESI, + ve 離子): 607.3 (M+H)⁺ 。 Step 6 : ( 3S )-4-(6 -fluoro -7-(2 -fluoro -6- hydroxyphenyl )-1-(2- isopropyl -4- methylpyridin -3- yl )-2 -oxo -1,2- dihydropyrido [2,3- d ] pyrimidin -4- yl )-3- methylpiperidin - 1- carboxylic acid tributyl ester. A mixture of ( S )-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl)-3-methylpiperidin-1-carboxylic acid tributyl ester (4.3 g, 8.1 mmol), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate ( intermediate Q , 2.9 g, 10.5 mmol), potassium acetate (3.2 g, 32.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (661 mg, 0.81 mmol) in 1,4-dioxane (80 mL) was degassed with nitrogen for 1 min. Deoxygenated water (14 mL) was added and the resulting mixture was heated at 90 °C for 1 h. The reaction was cooled to room temperature, quenched with half-saturated aqueous sodium bicarbonate, and extracted with EtOAc (2x) and DCM (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-60% 3:1 EtOAc-EtOH/heptane) to provide ( 3S )-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl)-3-methylpiperidin-1-carboxylic acid tributyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.19 (br s, 1 H), 8.38 (d, J = 5.0 Hz, 1 H), 8.26 (dd, J = 12.5, 9.2 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.18 (d, J = 5.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.68 (t, J = 8.9 Hz, 1 H), 4.77-4.98 (m, 1 H), 4.24 (br t, J = 14.2 Hz, 1 H), 3.93-4.08 (m, 1 H), 3.84 (br d, J =12.9 Hz, 1 H), 3.52-3.75 (m, 1 H), 3.07-3.28 (m, 1 H), 2.62-2.74 (m, 1 H), 1.86-1.93 (m, 3 H), 1.43-1.48 (m, 9 H), 1.35 (dd, J = 10.8, 6.8 Hz, 3 H), 1.26-1.32 (m, 1 H), 1.07 (dd, J = 6.6, 1.7 Hz, 3 H), 0.93 (dd, J = 6.6, 2.1 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ: -115.65 (s, 1 F), -128.62 (s, 1 F). m/z (ESI, + ve ion): 607.3 (M+H) ⁺ .

步驟 7 ： 6- 氟 -7-(2- 氟 -6- 羥基苯基 )-1-(4- 甲基 -2-(2- 丙烷基 )-3- 吡啶基 )-4-((2S )-2- 甲基 -4-(2- 丙烯醯基 )-1- 哌𠯤基 ) 吡啶并 [2,3-d ] 嘧啶 -2(1H)- 酮。將三氟乙酸（25 mL，324 mmol）添加(3S )-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基)-3-甲基哌𠯤-1-甲酸三級丁 基酯（6.3 g，10.4 mmol）在DCM（30 mL）中的溶液中。將所得混合物在室溫下攪拌1 h，然後濃縮。將殘餘物溶於DCM（30 mL）中，冷卻至0℃，並依次用DIPEA（7.3 mL，41.7 mmol）及丙烯醯氯（0.849 mL，10.4 mmol）的DCM（3 mL；藉由注射器逐滴添加）溶液處理。將反應物在0℃下攪拌10 min，然後用半飽和碳酸氫鈉水溶液淬滅，並用DCM萃取（2x）。將合併的有機層經無水硫酸鈉乾燥並濃縮。將殘餘物藉由矽膠層析（溶離液：0-100% 3 : 1 EtOAc-EtOH/庚烷）純化，以提供6-氟-7-(2-氟-6-羥苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S )-2-甲基-4-(2-丙烯醯基)-1-哌𠯤基)吡啶并[2,3-d ]嘧啶-2(1H)-酮。¹ H NMR（400 MHz, DMSO-d ₆ ）δppm 10.20（s, 1 H）, 8.39（d,J = 4.8 Hz, 1 H）, 8.24-8.34（m, 1 H）, 7.23-7.32（m, 1 H）, 7.19（d,J = 5.0 Hz, 1 H）, 6.87（td,J = 16.3, 11.0 Hz, 1 H）, 6.74（d,J = 8.6 Hz, 1 H）, 6.69（t,J = 8.6 Hz, 1 H）, 6.21（br d,J = 16.2 Hz, 1 H）, 5.74-5.80（m, 1 H）, 4.91（br s, 1 H）, 4.23-4.45（m, 2 H）, 3.97-4.21（m, 1 H）, 3.44-3.79 （m, 2 H）, 3.11-3.31（m, 1 H）, 2.67-2.77（m, 1 H）, 1.91（s, 3 H）, 1.35（d,J = 6.8 Hz, 3 H）, 1.08（d,J = 6.6 Hz, 3 H）, 0.94（d,J = 6.8 Hz, 3 H）。¹⁹ F NMR (376 MHz, DMSO-d₆ ) δ ppm -115.64 (s, 1 F), -128.63 (s, 1 F).m/z (ESI, +ve 離子）: 561.2 (M+H)⁺ 。 Step 7 : 6- Fluoro -7-(2 -fluoro -6- hydroxyphenyl )-1-(4 -methyl - 2- (2- propanyl )-3- pyridinyl )-4-(( 2S )-2- methyl -4-(2- propenyl )-1- piperidinyl ) pyrido [ 2,3- d ] pyrimidin -2(1H) -one. Trifluoroacetic acid (25 mL, 324 mmol) was added to a solution of ( 3S )-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl)-3-methylpiperidin-1-carboxylic acid tributyl ester (6.3 g, 10.4 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in DCM (30 mL), cooled to 0 °C, and treated sequentially with DIPEA (7.3 mL, 41.7 mmol) and acryloyl chloride (0.849 mL, 10.4 mmol) in DCM (3 mL; added dropwise via syringe). The reaction was stirred at 0 °C for 10 min, then quenched with semisaturated aqueous sodium bicarbonate and extracted with DCM (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-100% 3:1 EtOAc-EtOH/heptane) to provide 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-(( 2S )-2-methyl-4-(2-propenyl)-1-piperidinyl)pyrido[2,3- d ]pyrimidin-2(1H)-one. ¹ H NMR (400 MHz, DMSO- d ₆ ) δppm 10.20 (s, 1 H), 8.39 (d, J = 4.8 Hz, 1 H), 8.24-8.34 (m, 1 H), 7.23-7.32 (m, 1 H), 7.19 (d, J = 5.0 Hz, 1 H), 6.87 (td, J = 16.3, 11.0 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.69 (t, J = 8.6 Hz, 1 H), 6.21 (br d, J = 16.2 Hz, 1 H), 5.74-5.80 (m, 1 H), 4.91 (br s, 1 H), 4.23-4.45 (m, 2 H), 3.97-4.21 (m, 1 H), 3.44-3.79 (m, 2 H), 3.11-3.31 (m, 1 H), 2.67-2.77 (m, 1 H), 1.91 (s, 3 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm -115.64 (s, 1 F), -128.63 (s, 1 F). m/z (ESI, +ve ion): 561.2 (M+H) ⁺ .

本發明包括以下步驟，其中在步驟4及5中拆分外消旋-二酮促進阻轉異構物的成功分離： 方法描述 步驟 1 材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論 2,6-二氯-5-氟-3-吡啶甲酸 82671-06-5 209.99 1.0當量 119.1 25 kg DCM 74-09-2 84.93 16.51當量 2354.9 200 kg DMF 68-12-2 73.09 0.068當量 8.1 592 g（627 mL）草醯氯 79-37-8 126.93 1.25當量 148.9 18.9 kg 氫氧化銨 1336-21-6 35.05 5當量 595.5 40.2 L 水 7732-18-5 18.02 N/A N/A 261 L The present invention comprises the following steps, wherein resolution of the racemic-diketone in steps 4 and 5 promotes successful separation of the atropisomers: Method Description Step 1 Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory 2,6-Dichloro-5-fluoro-3-pyridinecarboxylic acid 82671-06-5 209.99 1.0 equivalent 119.1 25 kg DCM 74-09-2 84.93 16.51 equivalent 2354.9 200 kg DMF 68-12-2 73.09 0.068 equivalent 8.1 592 g (627 mL) Oxalic acid 79-37-8 126.93 1.25 equivalent 148.9 18.9 kg Ammonium hydroxide 1336-21-6 35.05 5 equivalent 595.5 40.2 L water 7732-18-5 18.02 N/A N/A 261 L

向2,6-二氯-5-氟-3-吡啶甲酸（化合物1）（25kg；119.1 mol）在二氯甲烷（167kg）及DMF（592g）中的溶液中添加草醯氯（18.9kg；148.9 mol），同時保持內部溫度在15-20℃之間。添加另外的二氯甲烷（33 kg）作為沖洗液，並將反應混合物攪拌2 h。冷卻反應混合物，然後用氫氧化銨（40.2 L；595.5 mol）淬滅，同時保持內部溫度為0 ± 10℃。將所得漿液攪拌90 min，然後藉由過濾收集產物。將過濾的固體用去離子水（3 × 87L）洗滌，乾燥，以提供2,6-二氯-5-氟煙醯胺（化合物2）。步驟 2 材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論醯胺（2,6-二氯-5-氟煙醯胺） 113237-20-0 209.99 1.0當量 77.8 16.27 kg 草醯氯 79-37-8 126.93 1.2當量 93.8 11.9 kg（7.9 L）二氯甲烷 75-09-2 84.93 N/A N/A 730.7 kg（551.5 L）苯胺DCM溶液 2-異丙基-4-甲基吡啶-3-胺 1698293-93-4 150.22 1.1當量 85.9 12.9 kg（含有苯胺的重量） To a solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (Compound 1) (25 kg; 119.1 mol) in dichloromethane (167 kg) and DMF (592 g) was added oxalyl chloride (18.9 kg; 148.9 mol) while maintaining the internal temperature between 15-20 °C. Additional dichloromethane (33 kg) was added as a rinse and the reaction mixture was stirred for 2 h. The reaction mixture was cooled and then quenched with ammonium hydroxide (40.2 L; 595.5 mol) while maintaining the internal temperature at 0 ± 10 °C. The resulting slurry was stirred for 90 min and the product was then collected by filtration. The filtered solid was washed with deionized water (3 x 87 L) and dried to provide 2,6-dichloro-5-fluoronicotineamide (Compound 2). Step 2 Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory Amide (2,6-dichloro-5-fluoronicotineamide) 113237-20-0 209.99 1.0 equivalent 77.8 16.27 kg Oxalic acid 79-37-8 126.93 1.2 equivalent 93.8 11.9 kg (7.9 L) Dichloromethane 75-09-2 84.93 N/A N/A 730.7 kg (551.5 L) Aniline DCM solution 2-isopropyl-4-methylpyridin-3-amine 1698293-93-4 150.22 1.1 Equivalent 85.9 12.9 kg (including weight of aniline)

在反應器A中，向2,6-二氯-5-氟煙醯胺（化合物2）（16.27kg；77.8 mol）的二氯甲烷（359.5kg）溶液添加草醯氯（11.9kg；93.8 mol），同時將溫度保持 ≤ 25℃長達75 min。然後將所得溶液加熱至40℃ ± 3℃並老化3 h。使用真空，蒸餾溶液以除去二氯甲烷，直到溶液在攪拌器以下。然後添加二氯甲烷（300 kg），並將混合物冷卻至0 ± 5℃。向乾淨的乾燥反應器（反應器B）中，添加2-異丙基-4-甲基吡啶-3-胺（苯胺）（12.9 kg；85.9 mol），隨後添加二氯甲烷（102.6 kg）。將苯胺溶液藉由真空蒸餾進行共沸乾燥，同時保持內部溫度在20-25℃之間，用另外的二氯甲烷替代，直至藉由KF分析將該溶液乾燥（極限值 ≤ 0.05%）。用二氯甲烷將溶液體積調節至約23 L體積。然後將乾燥的苯胺溶液添加到反應器A中，同時在整個添加過程中保持內部溫度為0 ± 5℃。然後將混合物加熱至23℃並老化1 h。將該溶液精細過濾至乾淨的反應器中，得到2,6-二氯-5-氟-N-((2-異丙基-4-甲基吡啶-3-基)胺基甲醯基)煙醯胺（化合物3）的DCM溶液並直接用於下一步。步驟 3 材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論脲，DCM溶液 2,6-二氯-5-氟-N -{[4-甲基-2-(丙烷-2-基)吡啶-3-基]胺基甲醯基}吡啶-3-甲醯胺 N/A 385.22 1.0當量 38.9 208.3 kg（含15 kg重量） 2-甲基四氫呋喃 ‎96-47-9 86.13 N/A N/A 308 kg（358 L）三級丁醇鈉 865-48-5 96.11 2.0當量 97.8 9.4 kg 氯化銨 12125-02-9 53.49 N/A 430 23.0 kg 鹽酸 7467-01-0 36.46 N/A 41 1.6 kg 硫酸鎂 7487-88-9 120.37 N/A 195 23.5 kg 氯化鈉 7647-14-5 58.44 N/A 282 16.5 kg 庚烷 142-82-5 100.21 N/A N/A 94 L 10%檸檬酸 75 kg In Reactor A, oxalyl chloride (11.9 kg; 93.8 mol) was added to a solution of 2,6-dichloro-5-fluoronicotinoamide (Compound 2) (16.27 kg; 77.8 mol) in dichloromethane (359.5 kg) while maintaining the temperature at ≤ 25 °C for 75 min. The resulting solution was then heated to 40 °C ± 3 °C and aged for 3 h. Using vacuum, the solution was distilled to remove dichloromethane until the solution was below the stirrer. Dichloromethane (300 kg) was then added and the mixture was cooled to 0 ± 5 °C. To a clean, dry reactor (Reactor B), 2-isopropyl-4-methylpyridin-3-amine (aniline) (12.9 kg; 85.9 mol) was added, followed by dichloromethane (102.6 kg). The aniline solution was azeotropically dried by vacuum distillation while maintaining the internal temperature between 20-25°C, replacing with additional dichloromethane until the solution was dry by KF analysis (limit ≤ 0.05%). The solution volume was adjusted to approximately 23 L volume with dichloromethane. The dry aniline solution was then added to reactor A while maintaining the internal temperature at 0 ± 5°C throughout the addition. The mixture was then heated to 23°C and aged for 1 h. The solution was finely filtered into the clean reactor to give a DCM solution of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)aminoformyl)nicotinamide (Compound 3) and used directly in the next step. Step 3 Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory Urea, DCM solution 2,6-dichloro-5-fluoro- N -{[4-methyl-2-(propan-2-yl)pyridin-3-yl]aminocarbonyl}pyridine-3-carboxamide N/A 385.22 1.0 equivalent 38.9 208.3 kg (including 15 kg weight) 2-Methyltetrahydrofuran 96-47-9 86.13 N/A N/A 308 kg (358 L) Sodium butoxide tertiary 865-48-5 96.11 2.0 equivalent 97.8 9.4 kg Ammonium chloride 12125-02-9 53.49 N/A 430 23.0 kg Hydrochloric acid 7467-01-0 36.46 N/A 41 1.6 kg Magnesium sulfate 7487-88-9 120.37 N/A 195 23.5 kg Sodium chloride 7647-14-5 58.44 N/A 282 16.5 kg Heptane 142-82-5 100.21 N/A N/A 94 L 10% citric acid 75 kg

使用真空蒸餾將2,6-二氯-5-氟-N -{[4-甲基-2-(丙烷-2-基)吡啶-3-基]胺基甲醯基}吡啶-3-甲醯胺（UREA（化合物3））（含有15kg；38.9 mol）的二氯甲烷溶液溶劑更換成2-MeTHF，同時保持內部溫度為20-25℃。將反應器體積調節至40 L，然後充入另外的2-MeTHF（105.4 kg）。添加三級丁醇鈉（9.4 kg；97.8 mol），同時保持5-10℃。將內容物溫熱至23℃並攪拌3 h。然後將內容物冷卻至0-5C，並添加氯化銨（23.0 kg；430 mol）在60 L去離子水中的溶液。將混合物溫熱至20 C，並添加去離子水（15L），並進一步老化30 min。停止攪拌並分離各層。除去水層，並向有機層中添加去離子水（81.7L）。製備濃HCl（1.5kg）及水（9L）的混合物，然後將其緩慢添加至反應器中，直到所測pH值在4-5之間為止。分離各層，並用2-MeTHF（42.2kg）反萃取水層。合併兩個有機層，並用10%檸檬酸溶液（75 kg）洗滌，隨後用水（81.7 L）及飽和NaCl（19.8 kg）的混合物洗滌。然後將有機層用飽和碳酸氫鈉（75kg）洗滌，若必要，重複進行以達到水溶液目標pH≥7.0。再次用鹽水（54.7kg）洗滌有機層，然後用硫酸鎂（5kg）乾燥。過濾混合物以除去硫酸鎂，用2-MeTHF（49.2kg）沖洗濾床。將合併的濾液及洗滌液在真空下蒸餾至40 L體積。將濃縮的溶液加熱至55℃，並緩慢添加庚烷（10-12kg）直至達到濁點。經2h將溶液冷卻至23℃，然後經2 h添加庚烷（27.3kg）。將產物漿液在20-25℃下老化3 h，然後過濾並用2-MeTHF（2.8 kg）及庚烷（9 kg）的混合物洗滌。使用氮氣及真空乾燥產物，得到固體7-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮（外消旋-二酮（化合物4））。步驟 4 材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論外消旋-二酮 N/A 348.76 1.0 (+)-2,3-二苯甲醯基-D-酒石酸 17026-42-5 358.30 2.0 2-甲基四氫呋喃 ‎96-47-9 86.13 7.0 庚烷 142-82-5 100.21 2.0 庚烷 142-82-5 100.21 3.0 2-甲基四氫呋喃 ‎96-47-9 86.13 4.0 庚烷 142-82-5 100.21 2.0 A solution of 2,6-dichloro-5-fluoro- N -{[4-methyl-2-(propan-2-yl)pyridin-3-yl]aminocarbonyl}pyridine-3-carboxamide (UREA (Compound 3)) (containing 15 kg; 38.9 mol) in dichloromethane was solvent exchanged to 2-MeTHF using vacuum distillation while maintaining an internal temperature of 20-25 °C. The reactor volume was adjusted to 40 L and then charged with additional 2-MeTHF (105.4 kg). Sodium tert-butoxide (9.4 kg; 97.8 mol) was added while maintaining 5-10 °C. The contents were warmed to 23 °C and stirred for 3 h. The contents were then cooled to 0-5°C and a solution of ammonium chloride (23.0 kg; 430 mol) in 60 L of deionized water was added. The mixture was warmed to 20°C and deionized water (15 L) was added and aged for a further 30 min. Stirring was stopped and the layers were separated. The aqueous layer was removed and deionized water (81.7 L) was added to the organic layer. A mixture of concentrated HCl (1.5 kg) and water (9 L) was prepared and slowly added to the reactor until the measured pH was between 4-5. The layers were separated and the aqueous layer was back extracted with 2-MeTHF (42.2 kg). The two organic layers were combined and washed with 10% citric acid solution (75 kg), followed by a mixture of water (81.7 L) and saturated NaCl (19.8 kg). The organic layer was then washed with saturated sodium bicarbonate (75 kg), and if necessary, the process was repeated to achieve a target pH ≥ 7.0 for the aqueous solution. The organic layer was washed again with brine (54.7 kg) and then dried with magnesium sulfate (5 kg). The mixture was filtered to remove magnesium sulfate and the filter bed was rinsed with 2-MeTHF (49.2 kg). The combined filtrate and washes were distilled under vacuum to a volume of 40 L. The concentrated solution was heated to 55 °C and heptane (10-12 kg) was slowly added until it reached cloudiness. The solution was cooled to 23 °C over 2 h and then heptane (27.3 kg) was added over 2 h. The product slurry was aged at 20-25 °C for 3 h and then filtered and washed with a mixture of 2-MeTHF (2.8 kg) and heptane (9 kg). The product was dried under nitrogen and vacuum to give solid 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (rac-dione (Compound 4)). Step 4 Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory Racemic-dione N/A 348.76 1.0 (+)-2,3-Diphenylcarbazyl-D-tartaric acid 17026-42-5 358.30 2.0 2-Methyltetrahydrofuran 96-47-9 86.13 7.0 Heptane 142-82-5 100.21 2.0 Heptane 142-82-5 100.21 3.0 2-Methyltetrahydrofuran ‎96-47-9 86.13 4.0 Heptane 142-82-5 100.21 2.0

在氮氣氛圍下，向容器中，向化合物4（1.0當量）在2-甲基四氫呋喃（7.0 L/kg）中的攪拌懸浮液添加(+)-2,3-二苯甲醯基-D-酒石酸（2.0當量）。2-MeTHF係對掌性的，但用作外消旋混合物。將2-MeTHF的不同鏡像異構物隨機摻入共晶體中。將所得懸浮液溫熱至75℃並在75℃下老化直至觀察到完全溶解（≤ 30 min）。將所得溶液在75℃下精細過濾至第二容器中。以保持內部溫度高於65℃的速率，向精細過濾的溶液中充入正庚烷（2.0 L/kg）。然後將溶液冷卻至60℃，用晶體（0.01 kg/kg）接種，並老化30分鐘。經4小時將所得懸浮液冷卻至20℃，然後取樣以藉由HPLC進行對掌性純度分析。向該懸浮液中充入正庚烷（3.0 L/kg），然後在氮氣氛圍下在20℃下老化4小時。將懸浮液過濾，並將分離的固體用（2:1）正庚烷:2-甲基四氫呋喃（3.0 L/kg）洗滌兩次。將該材料用氮氣及真空乾燥，得到間二酮:DBTA:Me-THF複合物（化合物4a）。步驟 5 材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論間二酮/DBTA/Me-THF共晶體 N/A 1228.08 1.0 74.2 46.9 kg （對於間二酮校正為25.9 kg）甲基三級丁基醚 1634-04-4 88.15 45.0 17593 2100 L 磷酸氫二鈉 7558-79-4 141.96 2.0 148.4 21.1 kg USP純淨水根據需要硫酸鎂 7487-88-9 120.37 N/A N/A 25 kg 庚烷 142-82-5 100.20 60.0 19322 2835 L To a stirred suspension of compound 4 (1.0 eq.) in 2-methyltetrahydrofuran (7.0 L/kg) in a container under nitrogen atmosphere was added (+)-2,3-diphenylcarbonyl-D-tartaric acid (2.0 eq.). 2-MeTHF is chiral but used as a racemic mixture. Different mirror image isomers of 2-MeTHF were randomly incorporated into the co-crystals. The resulting suspension was warmed to 75 °C and aged at 75 °C until complete dissolution was observed (≤ 30 min). The resulting solution was finely filtered at 75 °C into a second container. The finely filtered solution was charged with n-heptane (2.0 L/kg) at a rate to maintain the internal temperature above 65 °C. The solution was then cooled to 60°C, seeded with crystals (0.01 kg/kg), and aged for 30 minutes. The resulting suspension was cooled to 20°C over 4 hours and then sampled for chiral purity analysis by HPLC. The suspension was charged with n-heptane (3.0 L/kg) and then aged at 20°C for 4 hours under a nitrogen atmosphere. The suspension was filtered and the separated solid was washed twice with (2:1) n-heptane:2-methyltetrahydrofuran (3.0 L/kg). The material was dried with nitrogen and vacuum to give the meta-diketone:DBTA:Me-THF complex (Compound 4a). Step 5 Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory Diketone/DBTA/Me-THF cocrystal N/A 1228.08 1.0 74.2 46.9 kg (25.9 kg corrected for dione) Methyl tert-butyl ether 1634-04-4 88.15 45.0 17593 2100 L Sodium Hydrogen Phosphate 7558-79-4 141.96 2.0 148.4 21.1 kg USP Purified Water As needed Magnesium sulfate 7487-88-9 120.37 N/A N/A 25 kg Heptane 142-82-5 100.20 60.0 19322 2835 L

在容器A中，攪拌磷酸氫二鈉（21.1 kg，2.0當量）在去離子水（296.8 L，6.3 L/kg）中的懸浮液，直到觀察到溶解（≥ 30 min）。在容器B中，將間二酮:DBTA:Me-THF複合物（組成物4a）[46.9 kg（對於間二酮校正為25.9 kg，1.0當量）]在甲基三級丁基醚（517.8 L，11.0 L/kg）中的懸浮液攪拌15至30分鐘。將來自容器A的所得溶液添加至容器B，然後將混合物攪拌超過3小時。停止攪拌，並將雙相混合物分離超過30分鐘。除去下面的水相，然後用甲基三級丁基醚（77.7 L，1.7 L/kg）反萃取。將有機相在容器B中合併，並用硫酸鎂（24.8 kg，0.529 kg/kg）乾燥。將來自容器B的所得懸浮液攪拌超過三小時，並且然後過濾至容器C中。向容器B中充入甲基三級丁基醚（46.9 L，1.0 L/kg）沖洗液，並且然後過濾至容器C中。將容器C的內容物冷卻至10℃，然後在真空下蒸餾，同時緩慢溫熱至35℃。繼續蒸餾直到收集到320-350 kg（6.8-7.5 kg/kg）甲基三級丁基醚。將容器C的內容物冷卻至20℃後，經1小時充入正庚烷（278.7 L，5.9 L/kg），然後在真空下蒸餾，同時緩慢溫熱至35℃。繼續蒸餾直到收集到190-200 kg（4.1-4.3 kg/kg）的甲基三級丁基醚及正庚烷的混合物。將容器C中的內容物冷卻至20℃後，經1小時第二次充入正庚烷（278.7 L，5.9 L/kg），然後在真空下蒸餾，同時緩慢溫熱至35℃。繼續蒸餾直到收集到190-200 kg（4.1-4.3 kg/kg）的甲基三級丁基醚及正庚烷的混合物。將容器C的內容物冷卻至20℃後，經1小時第三次充入正庚烷（195.9 L，4.2 L/kg），然後採樣以藉由GC分析溶劑組成。繼續攪拌容器C的懸浮液超過一小時。過濾該懸浮液，然後用正庚烷（68.6 L，1.5 L/kg）沖洗液從容器C中洗滌。將分離的固體在50℃下乾燥，並提交樣本便於儲備。得到7-氯-6-氟-(1M)-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]吡啶并[2,3-d ]嘧啶-2,4(1H ,3H )-二酮（間二酮）化合物5M。In container A, a suspension of sodium hydrogen phosphate (21.1 kg, 2.0 eq.) in deionized water (296.8 L, 6.3 L/kg) was stirred until dissolution was observed (≥ 30 min). In container B, a suspension of meta-diketone:DBTA:Me-THF complex (composition 4a) [46.9 kg (25.9 kg, 1.0 eq. corrected for meta-diketone)] in methyl tert-butyl ether (517.8 L, 11.0 L/kg) was stirred for 15 to 30 min. The resulting solution from container A was added to container B, and the mixture was stirred for more than 3 h. Stirring was stopped, and the biphasic mixture was separated for more than 30 min. The lower aqueous phase was removed and then back-extracted with methyl tert-butyl ether (77.7 L, 1.7 L/kg). The organic phases were combined in vessel B and dried over magnesium sulfate (24.8 kg, 0.529 kg/kg). The resulting suspension from vessel B was stirred for more than three hours and then filtered into vessel C. Vessel B was charged with a rinse of methyl tert-butyl ether (46.9 L, 1.0 L/kg) and then filtered into vessel C. The contents of vessel C were cooled to 10°C and then distilled under vacuum while slowly warming to 35°C. Distillation was continued until 320-350 kg (6.8-7.5 kg/kg) of methyl tert-butyl ether was collected. After cooling the contents of container C to 20°C, n-heptane (278.7 L, 5.9 L/kg) was added over 1 hour, and then distilled under vacuum while slowly warming to 35°C. Distillation was continued until 190-200 kg (4.1-4.3 kg/kg) of a mixture of methyl tert-butyl ether and n-heptane was collected. After cooling the contents of container C to 20°C, n-heptane (278.7 L, 5.9 L/kg) was added for the second time over 1 hour, and then distilled under vacuum while slowly warming to 35°C. Distillation was continued until 190-200 kg (4.1-4.3 kg/kg) of a mixture of methyl tert-butyl ether and n-heptane was collected. After cooling the contents of container C to 20°C, n-heptane (195.9 L, 4.2 L/kg) was charged for the third time over 1 hour, and then sampled for analysis of the solvent composition by GC. The suspension in container C was continued to be stirred for more than 1 hour. The suspension was filtered and then washed from container C with n-heptane (68.6 L, 1.5 L/kg) rinse. The separated solid was dried at 50°C and a sample was submitted for storage. 7-Chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidine-2,4( 1H , 3H )-dione (meta-diketone) compound 5M was obtained.

以上突出顯示的第一代方法已成功按比例放大至200+ kg外消旋-二酮起始材料（化合物5）。在此方法中，用熱力學穩定的外消旋-二酮晶體形式（表現出低溶解度）接種會導致批次失敗。基於吾人的後續研究，吾人發現藉由調節庚烷進料時間表來提高DBTA當量並降低種子溫度，提高了方法的穩健性。改善的方法可抵抗熱力學穩定的外消旋-二酮晶體形式的存在，並促進阻轉異構物的成功分離。隨後的批次將合併改善的方法進行大規模製造。步驟 6 材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論間二酮 N/A 348.76 1當量 9.8 3.7 kg 甲苯 108-88-3 92.14 N/A 375 34.6 kg（40 L）磷醯氯 10025-87-3 153.33 1.2當量 11.7 1.8 kg （1.1 L） N,N-二異丙基乙胺 7087-68-5 129.24 3.0當量 29.4 3.8 kg （5.1 L） (s)-1-Boc-3-甲基哌𠯤 147081-29-6 200.28 1.1當量 10.8 2.214 kg 碳酸氫鈉 144-55-8 84.01 N/A N/A 973 g 二氯甲烷 75-09-2 84.93 N/A 871 74 kg （55.6 L）氯化鈉 7647-14-5 58.44 N/A 103 6.0 kg 乙酸乙酯 141-78-6 88.11 N/A 288 25.4 kg（28.2 L） The first generation method highlighted above has been successfully scaled up to 200+ kg of rac-dione starting material (Compound 5). In this method, seeding with a thermodynamically stable crystalline form of the rac-dione (which exhibits low solubility) resulted in batch failures. Based on our subsequent studies, we discovered that the robustness of the method was improved by adjusting the heptane feed schedule to increase the DBTA equivalent and reduce the seeding temperature. The improved method is resistant to the presence of the thermodynamically stable crystalline form of the rac-dione and promotes successful separation of the antropisomers. Subsequent batches will incorporate the improved method for large-scale manufacturing. Step 6 Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory Meta-diketone N/A 348.76 1 equivalent 9.8 3.7 kg Toluene 108-88-3 92.14 N/A 375 34.6 kg (40 L) Phosphate chloride 10025-87-3 153.33 1.2 equivalent 11.7 1.8 kg (1.1 L) N,N-Diisopropylethylamine 7087-68-5 129.24 3.0 equivalent 29.4 3.8 kg (5.1 L) (S)-1-Boc-3-methylpiperidinium 147081-29-6 200.28 1.1 Equivalent 10.8 2.214 kg Sodium bicarbonate 144-55-8 84.01 N/A N/A 973 g Dichloromethane 75-09-2 84.93 N/A 871 74 kg (55.6 L) Sodium chloride 7647-14-5 58.44 N/A 103 6.0 kg Ethyl acetate 141-78-6 88.11 N/A 288 25.4 kg (28.2 L)

將7-氯-6-氟-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]吡啶并[2,3-d ]嘧啶-2,4(1H ,3H )-二酮（間二酮）（3.7kg；9.8 mol）與10.5kg甲苯在反應器（A）中合併，蒸餾到只剩油以除去水，同時保持設定點為45℃。將甲苯（21kg）添加到殘餘物中，並將混合物在40-45℃下攪拌30 min。將內容物冷卻至22℃，然後添加磷醯氯（1.8 kg；11.7 mol）。將混合物冷卻至0-5℃，然後添加N,N-二異丙基乙胺（2.5 kg；19.34 mol），同時保持溫度＜ 5℃。將該溶液在22℃下老化3 h。在單獨的反應器（B）中，將(s)-1-boc-3-甲基哌𠯤（2.21kg；10.8 mol）及N,N-二異丙基乙胺（1.26kg；9.75 mol）合併在甲苯（6 kg）中，然後充入反應器（A）中，同時保持＜ 25℃。將反應混合物在22C下老化15 min，然後用碳酸氫鈉（973g）的水（12.9L）溶液淬滅，同時保持溫度＜ 25 C。將混合物攪拌30 min，然後添加DCM（36.8kg），同時繼續攪拌1 h。使各層分離，並將下部有機層排至反應器（C）。用DCM（18.4kg）反萃取反應器（A）中的水層，將合併的有機層用鹽水溶液（6.0 kg NaCl；16.5 kg去離子水）洗滌。將有機層在大氣壓下蒸餾，保持內部溫度在45-55C之間。在蒸餾過程中將DCM替代以共沸乾燥溶液。蒸餾後，使用DCM將溶液體積調節至19 L。將該溶液冷卻至30 C，並精細過濾。將濾液與乙酸乙酯（8.5 kg）合併，然後在大氣壓下蒸餾直到在接收器中收集到11-13 kg。將溶液用30g真品接種，然後在25-30℃下老化1 h，然後在45-55 C內部溫度下於大氣壓下進一步蒸餾，直到收集到8.2 kg餾出液為止。將漿液冷卻至22℃並老化過夜，然後進一步冷卻至0-5℃。藉由過濾收集產物，並用乙酸乙酯洗滌兩次（每次4.2 kg）。將濾餅用氮氣及真空乾燥，得到(3S )-4-{7-氯-6-氟-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基}-3-甲基哌𠯤-1-甲酸三級丁 酯（化合物6，PIPAZOLINE）。步驟 7 材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論 [1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II) 72287-26-4 731.714 0.020 1.01 0.74 kg 二氯甲烷 75-09-2 84.93 N/A 400 kg 1,4-二噁烷 123-91-1 88.1052 5.0 N/A 168 kg 乙二胺四乙酸二鈉二水合物 6381-92-6 336.207 1.0 45.2 15.2 kg 庚烷 142-82-5 100.21 200 kg 氮氣根據需要 Pipazoline N/A 531.0 1.0 45.2 24.0 kg 乙酸鉀 127-08-2 98.1417 5.0 225.99 22.2 kg 三氟(2-氟-6-羥基苯基)硼酸鉀 N/A 233.03 1.20 54.24 12.6 kg 2-丙醇 67-63-0 66.10 N/A 850 kg 矽硫醇 N/A N/A N/A 13.2 kg 氫氧化鈉 1310-73-2 40.00 6.5 kg USP純淨水根據需要 7-Chloro-6-fluoro-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidine-2,4(1 H ,3 H )-dione (meta-diketone) (3.7 kg; 9.8 mol) was combined with 10.5 kg toluene in reactor (A) and distilled to oil to remove water while maintaining the set point at 45°C. Toluene (21 kg) was added to the residue and the mixture was stirred at 40-45°C for 30 min. The contents were cooled to 22°C and then phosphatidyl chloride (1.8 kg; 11.7 mol) was added. The mixture was cooled to 0-5°C and N,N-diisopropylethylamine (2.5 kg; 19.34 mol) was then added while maintaining the temperature < 5°C. The solution was aged at 22°C for 3 h. In a separate reactor (B), (s)-1-boc-3-methylpiperidinium (2.21 kg; 10.8 mol) and N,N-diisopropylethylamine (1.26 kg; 9.75 mol) were combined in toluene (6 kg) and then charged to reactor (A) while maintaining < 25°C. The reaction mixture was aged at 22°C for 15 min and then quenched with a solution of sodium bicarbonate (973 g) in water (12.9 L) while maintaining the temperature < 25°C. The mixture was stirred for 30 min, then DCM (36.8 kg) was added while stirring was continued for 1 h. The layers were separated and the lower organic layer was drained to reactor (C). The aqueous layer in reactor (A) was back-extracted with DCM (18.4 kg) and the combined organic layers were washed with a saline solution (6.0 kg NaCl; 16.5 kg deionized water). The organic layer was distilled at atmospheric pressure, maintaining the internal temperature between 45-55°C. DCM was replaced during the distillation to azeotropically dry the solution. After distillation, the volume of the solution was adjusted to 19 L with DCM. The solution was cooled to 30°C and finely filtered. The filtrate was combined with ethyl acetate (8.5 kg) and then distilled at atmospheric pressure until 11-13 kg were collected in the receiver. The solution was inoculated with 30 g of the authentic product and then aged at 25-30 °C for 1 h and then further distilled at atmospheric pressure at 45-55 °C internal temperature until 8.2 kg of distillate was collected. The slurry was cooled to 22 °C and aged overnight and then further cooled to 0-5 °C. The product was collected by filtration and washed twice with ethyl acetate (4.2 kg each time). The filter cake was dried under nitrogen and vacuum to obtain ( 3S )-4-{7-chloro-6-fluoro-( 1M )-1-[4-methyl-2-(propane-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin-1-carboxylic acid tributyl ester (Compound 6, PIPAZOLINE). Step 7 Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) 72287-26-4 731.714 0.020 1.01 0.74 kg Dichloromethane 75-09-2 84.93 N/A 400 kg 1,4-Dioxane 123-91-1 88.1052 5.0 N/A 168 kg Disodium ethylenediaminetetraacetate dihydrate 6381-92-6 336.207 1.0 45.2 15.2 kg Heptane 142-82-5 100.21 200 kg Nitrogen As needed Pipazoline N/A 531.0 1.0 45.2 24.0 kg Potassium acetate 127-08-2 98.1417 5.0 225.99 22.2 kg Potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate N/A 233.03 1.20 54.24 12.6 kg 2-Propanol 67-63-0 66.10 N/A 850 kg Silicon mercaptans N/A N/A N/A 13.2 kg Sodium hydroxide 1310-73-2 40.00 6.5 kg USP Purified Water As needed

向反應器中添加脫氣的二噁烷（74.2 kg）、(3S )-4-{7-氯-6-氟-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基}-3-甲基哌𠯤-1-甲酸三級丁 酯（化合物6，Pipazoline）（24.0 kg，45.2 mol）、乙酸鉀（22.2 kg，45.2 mol）及(dppf)PdCl₂ （0.74 kg，1.01 mol）。將反應器用氮氣惰性化。向溶液中鼓泡入氮氣直至氧氣含量＜ 500 mg/L。將反應加熱至87.5 ℃。將三氟(2-氟-6-羥基苯基)硼酸鉀（12.6 kg，54.3 moL）在脫氣的二噁烷（49.4 kg）及脫氣的水（14.4 kg）中的含氧量＜ 500 mg/L的溶液轉移到反應中，保持內部溫度為82.5℃ ± 7.5℃。將反應調節至87.5℃ ± 1.5℃，並攪拌75 min ± 15 min。向反應器中充入1.0 M EDTA溶液（47.3 kg），隨後充入水（40.1 kg），同時保持內部溫度為85℃ ± 5℃。經＞ 2 h將反應混合物冷卻至20℃ ± 3℃，然後攪拌＞ 16 h。將反應物過濾，並將粗固體用水（3 × 120 kg）沖洗。將固體用庚烷（28.8 kg）及2-丙醇（33.1 kg）的混合物沖洗，然後在＜ 50℃下乾燥＞ 10 h。在乾淨的反應器中裝入粗固體及二氯甲烷（240 kg）。將內容物在20℃ ± 5℃下攪拌＞ 30 min。向反應器中添加矽硫醇（144 kg）及二氯甲烷（14.9 kg）。將反應物在20℃ ± 5℃下攪拌18 h。將反應物過濾並用二氯甲烷（84 kg）沖洗。蒸餾溶液，並將溶劑交換為2-丙醇。將反應加熱至60℃ ± 3℃，充入庚烷（108 kg），同時保持反應溫度為60℃ ± 3℃。將反應物攪拌45 min，然後冷卻並在20℃ ± 5℃下攪拌2.5 h。將反應物過濾並用50體積%庚烷/2-丙醇（61.9 kg）沖洗。將分離出的固體在＜ 50℃下乾燥＞ 12 h，得到(3S )-4-{6-氟-7-(2-氟-6-羥基苯基)-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基}-3-甲基哌𠯤-1-甲酸三級丁 酯（化合物7，BIARYL）。步驟 8 一般注釋： 所有當量及體積均參考BIARYL 7報告材料 CAS # MW （ g/mol ）當量 / 體積莫耳理論 BIARYL 7 NA 606.67 1.0當量 5.27 2.75 kg TFA 76-05-1 114.02 11當量 49.7 5.67 kg DCM 74-09-2 84.93 5體積 NA 13.71 L 甲醇 67-56-1 32.04 5體積 NA 13.71 L 水 7732-18-5 18.02 20體積 NA 54.8 L 碳酸鉀 584-08-7 138.20 18當量 94.91 11.24 kg DCM 74-09-2 84.93 1體積 NA 2.75 L 水 7732-18-5 18.02 10體積 NA 27.5 L 水 7732-18-5 18.02 10體積 NA 27.5 L Degassed dioxane (74.2 kg), ( 3S )-4-{7-chloro-6-fluoro-( 1M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin-1-carboxylic acid tributyl ester (Compound 6, Pipazoline) (24.0 kg, 45.2 mol), potassium acetate (22.2 kg, 45.2 mol), and (dppf) _PdCl2 (0.74 kg, 1.01 mol) were added to the reactor. The reactor was inertized with nitrogen. Nitrogen was bubbled into the solution until the oxygen content was < 500 mg/L. The reaction was heated to 87.5 °C. Transfer a solution of potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (12.6 kg, 54.3 mol) in degassed dioxane (49.4 kg) and degassed water (14.4 kg) with an oxygen content of < 500 mg/L to the reaction, maintaining an internal temperature of 82.5°C ± 7.5°C. Adjust the reaction to 87.5°C ± 1.5°C and stir for 75 min ± 15 min. Charge the reactor with 1.0 M EDTA solution (47.3 kg) followed by water (40.1 kg) while maintaining an internal temperature of 85°C ± 5°C. Cool the reaction mixture to 20°C ± 3°C over > 2 h and then stir for > 16 h. The reaction was filtered and the crude solid was washed with water (3 × 120 kg). The solid was washed with a mixture of heptane (28.8 kg) and 2-propanol (33.1 kg) and then dried at <50°C for >10 h. A clean reactor was charged with the crude solid and dichloromethane (240 kg). The contents were stirred at 20°C ± 5°C for >30 min. Silothiol (144 kg) and dichloromethane (14.9 kg) were added to the reactor. The reaction was stirred at 20°C ± 5°C for 18 h. The reaction was filtered and washed with dichloromethane (84 kg). The solution was distilled and the solvent was exchanged to 2-propanol. Heat the reaction to 60°C ± 3°C and charge with heptane (108 kg) while maintaining the reaction temperature at 60°C ± 3°C. Stir the reaction for 45 min, then cool and stir at 20°C ± 5°C for 2.5 h. Filter the reaction and rinse with 50% by volume heptane/2-propanol (61.9 kg). The separated solid was dried at <50°C for >12 h to obtain ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-( 1M )-1-[4-methyl-2-(propane-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin-1-carboxylic acid tributyl ester (Compound 7, BIARYL). Step 8 General Notes: All equivalents and volumes refer to BIARYL 7 report Material CAS # MW ( g/mol ) Equivalent / Volume Moore Theory BIARYL 7 NA 606.67 1.0 equivalent 5.27 2.75 kg TFA 76-05-1 114.02 11 equivalent 49.7 5.67 kg DCM 74-09-2 84.93 5 Volume NA 13.71 L Methanol 67-56-1 32.04 5 Volume NA 13.71 L water 7732-18-5 18.02 20 volume NA 54.8 L Potassium carbonate 584-08-7 138.20 18 equivalent 94.91 11.24 kg DCM 74-09-2 84.93 1 Volume NA 2.75 L water 7732-18-5 18.02 10 Volume NA 27.5 L water 7732-18-5 18.02 10 Volume NA 27.5 L

向反應器中添加(3S )-4-{6-氟-7-(2-氟-6-羥基苯基)-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]-2-側氧基-1,2-二氫吡啶并[2,3-d ]嘧啶-4-基}-3-甲基哌𠯤-1-甲酸三級丁 酯（化合物7，BIARYL）（2.75 kg，5.27 mol）、DCM（13.7 L）及TFA（5.67 kg，49.7 mol）。將反應物在20 ± 5℃下攪拌8-16 h。向第二反應器中添加碳酸鉀（11.24 kg）、水（54.8 L）及甲醇（13.7 L）以形成均勻溶液。經2 h將反應混合物添加碳酸鉀溶液中。將混合物在20 ± 5℃下再攪拌12 h。過濾所得漿液，並用水（2 × 27.5 L）沖洗。將濕濾餅乾燥24 h，得到6-氟-7-(2-氟-6-羥基苯基)-4-[(2S )-2-甲基哌𠯤-1-基]-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]吡啶并[2,3-d ]嘧啶-2(1H )-酮（化合物8，DESBOC）。步驟 9 一般注釋： 所有當量及體積均參考Des-BOC報告材料 CAS # MW （ g/mol ）當量 / 體積 mmol 質量體積 Des-BOS NA 506.56 1.0當量 308.4 156.25 g 丙烯醯氯^[1] 814-68-6 90.51 1.3當量 401.0 36.29 g - - NMP N-甲基吡咯啶酮^[2] 872-50-4 99.13 4體積 NA - 625 mL 水 7732-18-5 18.02 20體積 NA 3125 g 3125 mL Na₂ HPO4^[3] 7558-79-4 141.96 4當量 1233.6 175.12 g - 水 7732-18-5 18.02 20體積 NA 3125 g 3,125 mL To the reactor was added ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-( 1M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin-1-carboxylic acid tributyl ester (Compound 7, BIARYL) (2.75 kg, 5.27 mol), DCM (13.7 L) and TFA (5.67 kg, 49.7 mol). The reaction was stirred at 20 ± 5 °C for 8-16 h. Potassium carbonate (11.24 kg), water (54.8 L) and methanol (13.7 L) were added to the second reactor to form a homogeneous solution. The reaction mixture was added to the potassium carbonate solution over 2 h. The mixture was stirred at 20 ± 5 °C for another 12 h. The resulting slurry was filtered and rinsed with water (2 × 27.5 L). The wet cake was dried for 24 h to give 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2 S )-2-methylpiperidin-1-yl]-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one (Compound 8, DESBOC). Step 9 General Notes: All equivalents and volumes refer to Des-BOC reports Material CAS # MW ( g/mol ) Equivalent / Volume mmol Quality Volume Des-BOS NA 506.56 1.0 equivalent 308.4 156.25 g Acryloyl chloride ^[1] 814-68-6 90.51 1.3 equivalent 401.0 36.29 g - - NMP N-Methylpyrrolidone ^[2] 872-50-4 99.13 4 Volume NA - 625 mL water 7732-18-5 18.02 20 volume NA 3125 g 3125 mL _Na2HPO4 ^[3] 7558-79-4 141.96 4 equivalent 1233.6 175.12 g - water 7732-18-5 18.02 20 volume NA 3125 g 3,125 mL

將6-氟-7-(2-氟-6-羥基苯基)-4-[(2S )-2-甲基哌𠯤-1-基]-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]吡啶并[2,3-d ]嘧啶-2(1H )-酮（化合物8，DESBOC）（156.25 g）與N-甲基吡咯啶酮（625 mL）合併並在環境溫度下攪拌。向所得溶液中添加丙烯醯氯（36.29 g；401.0 mmoL），同時保持＜ 30℃內部溫度。在25 C下將內容物攪拌2 h。在單獨的反應器中，製備磷酸二鈉（175.1 g；1234 mmol）在去離子水（3.1 L）中的溶液。然後在25℃下經＞ 2 h將粗產物溶液轉移到含有磷酸二鈉溶液的反應器中。在添加到一半時中將漿液加熱至45℃，並且在完全添加之後，在相同溫度下老化2 h。將混合物冷卻至25 C並老化4 h，然後藉由真空過濾收集固體。用水洗滌固體兩次（每次1.5 L），將產物在氮氣及真空下乾燥，得到產物6-氟-7-(2-氟-6-羥基苯基)-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]-4-[(2S )-2-甲基-4-(丙-2-烯醯基)哌𠯤-1-基]吡啶并[2,3-d ]嘧啶-2(1H )-酮（粗製化合物9）。^[4] 步驟 10 一般注釋： 所有當量及體積均參考粗藥物物質報告材料 CAS # MW （ g/mol ）當量 / 體積 mmol 質量體積粗製化合物9 NA 560.60 1.0當量 253.9 142.33 g - 乙醇（200 proof） 64-17-5 - 7.5 V - - 1067 mL USP水 - 18.02 1.9 V - - 270 mL 乙酸 64-19-7 60.05 1.5當量 380.8 22.87 g 21.82 mL WFI水 - 18.02 15.5體積 - - 2200 mL 乙醇（用於洗滌） 64-17-5 - 2.5 V - - 356 mL WFI水（用於洗滌） - - 5.0 V - - 712 mL 化合物9種子^[5] - 560.60 0 - 0.3-0.7 g - 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin-1-yl]-( 1M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3 -d ]pyrimidin-2( 1H )-one (Compound 8, DESBOC) (156.25 g) was combined with N-methylpyrrolidone (625 mL) and stirred at ambient temperature. Acryloyl chloride (36.29 g; 401.0 mmol) was added to the resulting solution while maintaining an internal temperature of <30 °C. The contents were stirred at 25 °C for 2 h. In a separate reactor, prepare a solution of sodium phosphate (175.1 g; 1234 mmol) in deionized water (3.1 L). The crude product solution was then transferred to the reactor containing the sodium phosphate solution at 25 °C over > 2 h. The slurry was heated to 45 °C halfway through the addition and aged at the same temperature for 2 h after complete addition. The mixture was cooled to 25 °C and aged for 4 h before collecting the solid by vacuum filtration. The solid was washed twice with water (1.5 L each time), and the product was dried under nitrogen and vacuum to obtain the product 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2 S )-2-methyl-4-(prop-2-enyl)piperidin-1-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one (crude compound 9). ^[4] Step 10 General Notes: All equivalents and volumes refer to the crude drug substance report Material CAS # MW ( g/mol ) Equivalent / Volume mmol Quality Volume Crude compound 9 NA 560.60 1.0 equivalent 253.9 142.33 g - Ethanol (200 proof) 64-17-5 - 7.5 V - - 1067 mL USP Water - 18.02 1.9 V - - 270 mL Acetic acid 64-19-7 60.05 1.5 equivalent 380.8 22.87 g 21.82 mL WFI Water - 18.02 15.5 Volume - - 2200 mL Ethanol (for washing) 64-17-5 - 2.5 V - - 356 mL WFI water (for washing) - - 5.0 V - - 712 mL Compound 9 seed ^[5] - 560.60 0 - 0.3-0.7 g -

將6-氟-7-(2-氟-6-羥基苯基)-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]-4-[(2S )-2-甲基-4-(丙-2-烯醯基)哌𠯤-1-基]吡啶并[2,3-d ]嘧啶-2(1H )-酮（粗製化合物9）（142.33g；253.9 mmol）與乙醇（996 mL）及水（270 mL）合併。添加乙酸（21.8ml；380.8mmol），並將混合物加熱至75℃以形成溶液，將其精細過濾至乾淨的反應器中。將該溶液冷卻至45℃，然後添加水（1067 mL），同時保持內部溫度＞ 40℃。將該溶液用已證實的化合物9接種，將所得混合物老化30 min。然後經2 h添加水（1138 mL）。將混合物冷卻至25℃並老化8 h，然後藉由真空過濾收集固體，並使用乙醇（355.8 mL）及水（711.6 mL）的混合物洗滌。使用真空及氮氣乾燥固體，以獲得6-氟-7-(2-氟-6-羥基苯基)-(1M )-1-[4-甲基-2-(丙烷-2-基)吡啶-3-基]-4-[(2S )-2-甲基-4-(丙-2-烯醯基)哌𠯤-1-基]吡啶并[2,3-d ]嘧啶-2(1H )-酮（化合物9）。步驟 A1 反應方案 及進料表 材料 CAS # MW （ g/mol ）當量 / 體積 mol 質量（ g ） 體積（ L ） 3-氟苯甲醚 456-49-5 126.13 1.0 1.19 150 0.136 正丁基鋰（2.5 M 己烷） 109-72-8 64.06 1.5 1.78 N/A 0.712 二異丙胺 108-18-9 101.19 1.4 1.66 168 0.233 硼酸三乙酯 150-46-9 145.99 2.0 2.38 347.5 0.405 四氫呋喃 109-99-9 72.11 12體積 N/A N/A 1.8 鹽酸（2N） 7647-01-0 36.46 10體積 N/A N/A 1.5 甲基三級丁基醚 1634-04-4 88.15 12體積 N/A N/A 1.8 庚烷 142-82-5 100.20 10.5體積 N/A N/A 1.575 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2 S )-2-methyl-4-(prop-2-enyl)piperidin-1-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one (crude compound 9) (142.33 g; 253.9 mmol) was combined with ethanol (996 mL) and water (270 mL). Acetic acid (21.8 ml; 380.8 mmol) was added and the mixture was heated to 75°C to form a solution which was finely filtered into a clean reactor. The solution was cooled to 45°C and then water (1067 mL) was added while maintaining the internal temperature > 40°C. The solution was inoculated with confirmed compound 9 and the resulting mixture was aged for 30 min. Water (1138 mL) was then added over 2 h. The mixture was cooled to 25 °C and aged for 8 h, then the solid was collected by vacuum filtration and washed with a mixture of ethanol (355.8 mL) and water (711.6 mL). The solid was dried using vacuum and nitrogen to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2 S )-2-methyl-4-(prop-2-enyl)piperidin-1-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one (Compound 9). Step A1 Reaction Scheme and Feed Table Material CAS # MW ( g/mol ) Equivalent / Volume mol Mass ( g ) Volume ( L ) 3-Fluoroanisole 456-49-5 126.13 1.0 1.19 150 0.136 n-Butyl lithium (2.5 M in hexane) 109-72-8 64.06 1.5 1.78 N/A 0.712 Diisopropylamine 108-18-9 101.19 1.4 1.66 168 0.233 Triethyl borate 150-46-9 145.99 2.0 2.38 347.5 0.405 Tetrahydrofuran 109-99-9 72.11 12 Volume N/A N/A 1.8 Hydrochloric acid (2N) 7647-01-0 36.46 10 Volume N/A N/A 1.5 Methyl tert-butyl ether 1634-04-4 88.15 12 Volume N/A N/A 1.8 Heptane 142-82-5 100.20 10.5 Volume N/A N/A 1.575

向反應器A中充入THF（6體積）及二異丙胺（1.4當量）。將所得溶液冷卻至-70℃，並緩慢添加n-BuLi（2.5 M己烷，1.5當量）。加完後，緩慢添加3-氟苯甲醚（1.0當量）在THF（6體積）中的溶液，並在-70℃下保持5 min。緩慢添加B(EtO)₃ （2.0當量），並在-70℃下保持10 min。將反應混合物用2N HCl淬滅。用MTBE（3 × 4體積）萃取淬滅的反應混合物。將合併的有機相濃縮至1.5〜3總體積。逐滴添加庚烷（7-9體積），並將混合物冷卻至0-10℃，攪拌3 h。將混合物過濾並用庚烷（1.5體積）沖洗。將固體在＜ 30℃下在氮氣下乾燥，得到(2-氟-6-甲氧基苯基)酉朋酸。步驟 A2 反應方案及進料表 材料 CAS # MW （ g/mol ）當量 / 體積 mol 質量（ g ） 體積（ L ） (2-氟-6-甲氧基苯基)酉朋酸。 78495-63-3 169.95 1.0 0.118 20 N/A 三溴化硼 10294-33-4 250.52 1.5 0.177 44.2 0.017 二氯甲烷 75-09-2 84.93 4體積 N/A N/A 0.080 水 7732-18-5 18.02 13體積 N/A N/A 0.26 甲基三級丁基醚 1634-04-4 88.15 13體積 N/A N/A 0.26 庚烷 142-82-5 100.20 10體積 N/A N/A 0.20 Reactor A was charged with THF (6 vol) and diisopropylamine (1.4 eq). The resulting solution was cooled to -70 °C and n-BuLi (2.5 M in hexanes, 1.5 eq) was slowly added. After the addition was complete, a solution of 3-fluoroanisole (1.0 eq) in THF (6 vol) was slowly added and kept at -70 °C for 5 min. B(EtO) ₃ (2.0 eq) was slowly added and kept at -70 °C for 10 min. The reaction mixture was quenched with 2N HCl. The quenched reaction mixture was extracted with MTBE (3 × 4 vol). The combined organic phases were concentrated to 1.5~3 total volumes. Heptane (7-9 vol) was added dropwise and the mixture was cooled to 0-10 °C and stirred for 3 h. The mixture was filtered and rinsed with heptane (1.5 vol). The solid was dried under nitrogen at < 30 °C to give (2-fluoro-6-methoxyphenyl)phenylcarboxylic acid. Step A2 Reaction Scheme and Feed Table Material CAS # MW ( g/mol ) Equivalent / Volume mol Mass ( g ) Volume ( L ) (2-Fluoro-6-methoxyphenyl)phenylcarboxylic acid. 78495-63-3 169.95 1.0 0.118 20 N/A Boron tribromide 10294-33-4 250.52 1.5 0.177 44.2 0.017 Dichloromethane 75-09-2 84.93 4 Volume N/A N/A 0.080 water 7732-18-5 18.02 13 Volume N/A N/A 0.26 Methyl tert-butyl ether 1634-04-4 88.15 13 Volume N/A N/A 0.26 Heptane 142-82-5 100.20 10 Volume N/A N/A 0.20

向反應器A中充入二氯甲烷（4體積）及2-氟-6-甲氧基-4-甲基苯基酉朋酸（1當量）。將反應混合物冷卻至-30℃，並逐滴添加1.5 BBr₃ （1.5當量）。加完後，將混合物溫熱至25℃，並攪拌2 h。將反應混合物在冰冷的（0-5℃）水（10體積）中淬滅。添加MTBE（10體積），將混合物溫熱至25℃，並攪拌1-2 h或直至所有固體溶解。分離水相，並用MTBE（3體積）萃取。用水（3體積）洗滌合併的有機萃取物，然後濃縮至1總體積。將庚烷（10體積）添加到混合物中並攪拌2 h。藉由過濾分離所得產物，並在＜ 30℃下乾燥，得到(2-氟-6-羥基苯基)酉朋酸。步驟 A3 反應方案及進料表 材料 CAS # MW （ g/mol ）當量 / 體積 mol 質量（ kg ） 體積（ L ） (2-氟-6-羥基苯基)酉朋酸 1256345-60-4 155.92 1.0 89.79 14.00 N/A 檸檬酸一水合物 5949-29-1 210.14 1.64 147.26 30.94 N/A 乙腈 75-05-8 41.05 21 Vol N/A 220.1 294 氟化鉀 7789-23-3 58.10 4.00 359.16 20.87 N/A USP水 7732-18-5 18.02 2.0體積 N/A 28.00 28.00 矽藻土 N/A N/A N/A N/A 7.00 N/A 2-丙醇 67-63-0 60.10 25體積 N/A 275 350 步驟 A3 Reactor A was charged with dichloromethane (4 vol) and 2-fluoro-6-methoxy-4-methylphenylbenzoic acid (1 eq). The reaction mixture was cooled to -30 °C and 1.5 BBr ₃ (1.5 eq) was added dropwise. After the addition was complete, the mixture was warmed to 25 °C and stirred for 2 h. The reaction mixture was quenched into ice-cold (0-5 °C) water (10 vol). MTBE (10 vol) was added and the mixture was warmed to 25 °C and stirred for 1-2 h or until all solids were dissolved. The aqueous phase was separated and extracted with MTBE (3 vol). The combined organic extracts were washed with water (3 vol) and then concentrated to 1 total volume. Heptane (10 vol) was added to the mixture and stirred for 2 h. The resulting product was isolated by filtration and dried at < 30 °C to give (2-fluoro-6-hydroxyphenyl)benzoic acid. Step A3 Reaction Scheme and Feed Table Material CAS # MW ( g/mol ) Equivalent / Volume mol Mass ( kg ) Volume ( L ) (2-Fluoro-6-hydroxyphenyl)benzene 1256345-60-4 155.92 1.0 89.79 14.00 N/A Citric acid monohydrate 5949-29-1 210.14 1.64 147.26 30.94 N/A Acetonitrile 75-05-8 41.05 21 Vol N/A 220.1 294 Potassium fluoride 7789-23-3 58.10 4.00 359.16 20.87 N/A USP Water 7732-18-5 18.02 2.0 Volume N/A 28.00 28.00 Diatomaceous earth N/A N/A N/A N/A 7.00 N/A 2-Propanol 67-63-0 60.10 25 volume N/A 275 350 Step A3

在反應器（反應器A）中將氟化鉀（21.0 kg；20.87 mol）與水（28 L）合併，並將內容物攪拌30 min。在單獨的反應器（反應器B）中，在25 C下充入(2-氟-6-羥基苯基)酉朋酸（14.00 kg，89.79 mol），隨後充入乙腈（206.1 kg）及檸檬酸（30.94 kg；147.26 mol）。在25C下將反應器A的內容物添加至反應器B中，並在該溫度下攪拌10 h。經矽藻土床（7.0kg）過濾反應混合物，並用乙腈（42 kg）沖洗。將濾液與異丙醇（56 kg）合併，然後在真空下在＜ 35℃的溫度下蒸餾，用異丙醇替代反應器的蒸餾體積，並根據需要重複進行以完成從乙腈到異丙醇的溶劑交換。將漿液冷卻至15C並老化1 h，然後過濾並用28kg異丙醇洗滌。使用真空及氮氣乾燥濾餅並包裝，得到化合物A3。間二酮化合物 5 的拆分 間二酮中間體的層析拆分 Potassium fluoride (21.0 kg; 20.87 mol) was combined with water (28 L) in a reactor (reactor A) and the contents were stirred for 30 min. In a separate reactor (reactor B), (2-fluoro-6-hydroxyphenyl)benzoic acid (14.00 kg, 89.79 mol) was charged at 25 °C, followed by acetonitrile (206.1 kg) and citric acid (30.94 kg; 147.26 mol). The contents of reactor A were added to reactor B at 25 °C and stirred at this temperature for 10 h. The reaction mixture was filtered through a bed of diatomaceous earth (7.0 kg) and rinsed with acetonitrile (42 kg). The filtrate was combined with isopropanol (56 kg) and then distilled under vacuum at a temperature of < 35 °C, replacing the distillate volume of the reactor with isopropanol and repeating as needed to complete the solvent exchange from acetonitrile to isopropanol. The slurry was cooled to 15 °C and aged for 1 h, then filtered and washed with 28 kg of isopropanol. The filter cake was dried using vacuum and nitrogen and packaged to obtain compound A3. Resolution of dione compound 5 Chromatographic resolution of dione intermediates

使用了許多對掌性層析技術及方法以從化合物4中分離間二酮。該技術及固定相在本領域中係熟知的，並列於表1中。化合物4 [表 1 ] 技術固定相流動相產率^ SFC Chiralpak® AD 40%甲醇/ 60% CO2 * 約95% HPLC Chiralpak® AD 90/10/0.1 乙醇/甲醇/三乙胺約94% HPLC Chiralpak® IG 60/40/0.1 乙醇/甲醇/三乙胺約92% 模擬移動床（SMB） Chiralpak® IC 乙腈約96% ^產率定義為以＞ 98%ee的所需純度回收的可用間二酮的%。 *該分離進行了多次。對於每批材料，可能已對流動相進行了稍微修改，以適應批次中的變化。用於純化的其他流動相包括： 1) 25/75 甲醇/CO₂ ， 2) 30/70 甲醇/CO₂ ，以及 3) 50/50 甲醇/CO₂ 。A number of chiral chromatography techniques and methods were used to separate the meta-diketone from compound 4. The techniques and stationary phases are well known in the art and are listed in Table 1. Compound 4 [ Table 1 ] Technology Stationary Phase Mobile phase Yield^ SFC Chiralpak® AD 40% Methanol / 60% CO2 * About 95% HPLC Chiralpak® AD 90/10/0.1 ethanol/methanol/triethylamine About 94% HPLC Chiralpak® IG 60/40/0.1 ethanol/methanol/triethylamine About 92% Simulated Mobile Bed (SMB) Chiralpak® IC Acetonitrile About 96% ^Yield defined as % of available meta-diketone recovered at desired purity > 98%ee *This separation was performed multiple times. The mobile phase may have been modified slightly for each batch of material to accommodate variations in the batch. Other mobile phases used for purification include: 1) 25/75 methanol/ _CO2 , 2) 30/70 methanol/ _CO2 , and 3) 50/50 methanol/ _CO2 .

SFC、HPLC及SMB技術係本領域熟知的，並且Chiralpak®固定相可購自商業來源，例如飛世爾科技公司（Fisher Scientific）及大賽璐公司（Daicel Corporation）。SFC, HPLC, and SMB techniques are well known in the art, and Chiralpak® stationary phases are available from commercial sources such as Fisher Scientific and Daicel Corporation.

然而，期望開發出更有效的方法來分離間二酮（化合物5）。經典拆分 However, it is desirable to develop more efficient methods for the separation of meta-diketones ( compound 5).

本發明關於用於間/對-二酮外消旋物（化合物4）的可行的經典拆分方法的開發。The present invention relates to the development of a feasible classical resolution method for meta-/para-diketone racemates (compound 4).

總共進行了100次共晶體篩選實驗，並鑒定出三種潛在的二酮的共晶。基於殘留固體中，間/對-二酮的最高面積比及上清液中的最低面積比，選擇(+)-2,3-二苯甲醯基-D-酒石酸（DBTA）作為對掌性試劑進行拆分。A total of 100 cocrystal screening experiments were performed and three potential diketone cocrystals were identified. (+)-2,3-Dibenzoyl-D-tartaric acid (DBTA) was selected as the chiral reagent for resolution based on the highest area ratio of meta-/para-diketone in the residual solid and the lowest area ratio in the supernatant.

根據100次共晶體篩選實驗及20次更多的溶劑篩選的結果，發現2-MeTHF/正庚烷比其他溶劑系統提供更好的拆分結果。基於間二酮共晶體及對二酮共晶體在不同比例的2-MeTHF及正庚烷下的溶解度結果，選擇2-MeTHF/正庚烷（1.4：1，v/v）作為最佳溶劑組成物進行拆分。Based on the results of 100 cocrystal screening experiments and 20 more solvent screenings, it was found that 2-MeTHF/n-heptane provided better separation results than other solvent systems. Based on the solubility results of the meta-diketone cocrystals and para-diketone cocrystals in different ratios of 2-MeTHF and n-heptane, 2-MeTHF/n-heptane (1.4:1, v/v) was selected as the best solvent composition for separation.

為了找出對掌性拆分結晶過程中轉化為二酮外消旋物或間/對-二酮的任何可能形式，確定間二酮共晶體、對二酮共晶體、間+對-二酮共晶體混合物（1:1，w/w）、二酮外消旋物及DBTA在不同溫度下在2-MeTHF/正庚烷（1.4:1，v/v）中的溶解度。在不同溫度下持續7天未觀察到間二酮共晶體及對二酮共晶體的形式變化。但是，在不同溫度下將間+對-二酮共晶體混合物（1:1，w/w）的混合物攪拌7天後，獲得C型二酮外消旋物。在相應溫度下攪拌二酮外消旋物7天後，觀察到D型二酮外消旋物（20及30℃）或C型二酮外消旋物（40、50、60及65℃）。在所有溫度下，觀察到DBTA的溶解度均為約100 mg/mL。In order to find out any possible forms of conversion to dione racemate or m/p-diketone during the chiral resolution crystallization process, the solubility of m-diketone cocrystal, p-diketone cocrystal, m+p-diketone cocrystal mixture (1:1, w/w), dione racemate and DBTA in 2-MeTHF/n-heptane (1.4:1, v/v) at different temperatures was determined. No form change of m-diketone cocrystal and p-diketone cocrystal was observed for 7 days at different temperatures. However, after stirring the mixture of m+p-diketone cocrystal mixture (1:1, w/w) at different temperatures for 7 days, type C dione racemate was obtained. After stirring the diketone racemate at the respective temperature for 7 days, the diketone racemate D (20 and 30 °C) or the diketone racemate C (40, 50, 60, and 65 °C) was observed. At all temperatures, the solubility of DBTA was observed to be approximately 100 mg/mL.

為了進一步優化拆分過程，基於平衡溶解度結果繪製了間/對-二酮共晶體之三元相圖，並且未獲得共晶點，這可能是因為當存在間二酮共晶體及對二酮共晶體時，C型外消旋物會結晶出來。基於平衡溶解度結果繪製了間/對-二酮的另一個三元相圖，並且未獲得共晶點，這可能是因為當存在間二酮共晶及對二酮時，C型或D型二酮外消旋物會結晶出來。To further optimize the resolution process, a ternary phase diagram of the meta/para-diketone eutectic was drawn based on the equilibrium solubility results, and no eutectic point was obtained, which may be because the C-type racemate crystallized when the meta-diketone eutectic and the para-diketone eutectic were present. Another ternary phase diagram of the meta/para-diketone was drawn based on the equilibrium solubility results, and no eutectic point was obtained, which may be because the C-type or D-type diketone racemate crystallized when the meta-diketone eutectic and the para-diketone were present.

總之，已鑒定出用於拆分二酮外消旋物的對掌性試劑（DBTA）及溶劑系統（（2-MeTHF/正庚烷（1.4：1，v/v））。使用該拆分試劑及溶劑系統進行小規模結晶過程，對間二酮的產率可達39%，ee純度可達99%。另外，在篩選實驗中觀察及研究了二酮外消旋物的多態性。2 篩選實驗 2.1 共晶體篩選 In summary, a chiral reagent (DBTA) and solvent system ((2-MeTHF/n-heptane (1.4:1, v/v)) for the resolution of diketone racemates have been identified. Using this resolution reagent and solvent system for small-scale crystallization, the yield of meta-diketone can reach 39% and the ee purity can reach 99%. In addition, the polymorphism of diketone racemates was observed and studied in the screening experiment. 2 Screening Experiments 2.1 Cocrystal Screening

使用20種酸及5種溶劑系統進行了總共100次共晶體篩選實驗（結果總結在表2-1中）。通常，將莫耳比為1:1的二酮外消旋物及酸混合並在室溫下攪拌3天，然後分離進行XRPD。基於XRPD結果，鑒定了可能形成二酮外消旋物的共晶體的三種潛在酸，包括(1S)-(−)-樟腦酸（圖2-2），(+)-2,3-二苯甲醯基-D-酒石酸（圖2-3）及D-(+)-蘋果酸（圖2-4）。基於XRPD結果，亦獲得了四種新的游離鹼晶體形式，將其指定為B〜E型二酮外消旋物。A total of 100 cocrystal screening experiments were conducted using 20 acids and 5 solvent systems (the results are summarized in Table 2-1). Typically, the dione racemate and acid were mixed at a molar ratio of 1:1 and stirred at room temperature for 3 days before separation for XRPD. Based on the XRPD results, three potential acids that could form cocrystals of the dione racemate were identified, including (1S)-(−)-camphoric acid (Figure 2-2), (+)-2,3-dibenzoyl-D-tartaric acid (Figure 2-3), and D-(+)-malic acid (Figure 2-4). Based on the XRPD results, four new free base crystal forms were also obtained, which were designated as B~E dione racemates.

如表2-2所示，藉由HPLC進一步測試了三種潛在共晶體的上清液及殘餘固體。量測了間二酮/對二酮的比率，並總結在表2-2中。結果，DBTA共晶體顯示在上清液中的間二酮/對二酮的面積比為0.11，並且在殘留固體中為4.4，這表明間二酮及對二酮在用DBTA形成共晶體後顯示出良好的拆分。因此，選擇DBTA作為對掌性試劑用於進一步的拆分優化。 [表 2-1 ]共晶體篩選實驗的總結 溶劑酸丙酮 H₂ O/ACN （ 1 : 1 ， v/v ） EtOAc 2-MeTHF/ 正庚烷（ 1 : 1 ， v/v ） MTBE/ 正庚烷（ 1 : 1 ， v/v ）空白 B⁺ 型 C⁺ 型 C⁺ 型 D⁺ 型 E⁺ 型 L-天冬胺酸 B型 C型 C型+酸 D型 E型 (R)-1,4-苯并二噁烷-2-甲酸 B型 C型 C型 D型 E型+酸 (1S)-(−)-樟腦酸 B型 C型 A* 型共晶體 B* 型共晶體 A* 型共晶體 (−)-樟腦酸 B型 C型+酸 C型+酸 D型 E型+酸 (+)-2,3-二苯甲醯基-D-酒石酸 B型 C型非晶形 A^# 型共晶體 A^# 型共晶體 D-麩胺酸 B型 C型 C型+酸 D型 E型 D-(+)-蘋果酸 B型 C型 A^$ 型共晶體 D型 E型 (R)-(−)-扁桃酸 B型 C型 C型 D型 E型+酸 (−)-薄荷基氧乙酸 B型 C型 C型 D型 E型 (S)-(+)-α-甲氧基苯乙酸 B型 C型 C型 D型 E型 (R)-(+)-α-甲氧基-α-三氟甲基苯乙酸 B型 C型 C型 D型 E型 (R)-(−)-5-側氧基-2-四氫呋喃甲酸 B型 C型 C型 D型 E型 (R)-(+)-N-(1-苯乙基)琥珀酸 B型 C型 C型 D型 E型+酸 (S)-(+)-2-苯丙酸 B型 C型 C型 D型 E型 L-焦麩胺酸 B型 C型 C型 D型 E型+酸 D-(−)-奎寧酸 B型+酸 C型 C型+酸 D型+酸 E型+酸 L-(+)-酒石酸 B型 C型 C型 D型 E型 L-抗壞血酸 B型+酸 C型 C型+酸 D型 E型 N,N-雙[(R)-(−)-1-苯乙基]鄰胺甲醯苯甲酸 B型 C型 C型 D型 E型+酸 (S)-苯基琥珀酸 B型 C型 C型+酸 D型 E型+酸 ⁺ 表示游離外消旋-二酮的晶體形式（未形成共晶體），*：(1S)-(−)-樟腦酸共晶體， ^# ：(+)-2,3-二苯甲醯基-D-酒石酸共晶體， ^$ ：D-(+)-蘋果酸共晶體 [表 2-2 ]三種共晶體的 HPLC 資料總結 峰面積 樣本 上清液 固體對二酮（面積）間二酮（面積） M/P 對二酮（面積）間二酮（面積） M/P (1S)-(-)-樟腦酸共晶體A型（810465-06-C3） 9021.4 8274.2 0.9 6418.6 6360.4 1.0 (1S)-(-)-樟腦酸共晶體B型（810465-06-D3） 4673.2 4303.4 0.9 4768.3 4736.9 1.0 DBTA共晶體A型（810465-06-D5） 17673.1 1858.6 0.11 1180.2 5249.8 4.4 D-(+)-蘋果酸共晶體A型（810465-06-C7） 11382.6 10696.5 0.9 6443.3 6366.7 1.0 2.2 溶劑篩選 As shown in Table 2-2, the supernatant and residual solid of three potential co-crystals were further tested by HPLC. The ratio of meta-diketone/para-diketone was measured and summarized in Table 2-2. As a result, the DBTA co-crystal showed a meta-diketone/para-diketone area ratio of 0.11 in the supernatant and 4.4 in the residual solid, which indicated that meta-diketone and para-diketone showed good resolution after forming co-crystals with DBTA. Therefore, DBTA was selected as the chiral reagent for further resolution optimization. [ Table 2-1 ] Summary of co-crystal screening experiments Solvent Acid acetone H ₂ O/ACN ( 1:1 , v/v ) EtOAc 2-MeTHF/ n-heptane ( 1:1 , v/v ) MTBE/ n-heptane ( 1:1 , v/v ) blank Type B ⁺ C ⁺ Type C ⁺ Type D ⁺ Type E ⁺ Type L-Aspartic Acid Type B Type C C type + acid Type D Type E (R)-1,4-Benzodioxane-2-carboxylic acid Type B Type C Type C Type D E type + acid (1S)-(−)-Camphoric acid Type B Type C A* type eutectic B* type eutectic A* type eutectic (−)-Camphoric acid Type B C type + acid C type + acid Type D E type + acid (+)-2,3-Diphenylcarbazyl-D-tartaric acid Type B Type C Amorphous A ^# type eutectic A ^# type eutectic D-Glutamine Type B Type C C type + acid Type D Type E D-(+)-Apple acid Type B Type C A ^$ type eutectic Type D Type E (R)-(−)-Mandelic acid Type B Type C Type C Type D E type + acid (−)-Menthyloxyacetic acid Type B Type C Type C Type D Type E (S)-(+)-α-Methoxyphenylacetic acid Type B Type C Type C Type D Type E (R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid Type B Type C Type C Type D Type E (R)-(−)-5-O-oxo-2-tetrahydrofurancarboxylic acid Type B Type C Type C Type D Type E (R)-(+)-N-(1-Phenylethyl)succinic acid Type B Type C Type C Type D E type + acid (S)-(+)-2-Phenylpropionic acid Type B Type C Type C Type D Type E L-Pyroglutamic acid Type B Type C Type C Type D E type + acid D-(−)-Quinic acid B type + acid Type C C type + acid D-type + acid E type + acid L-(+)-Tartaric acid Type B Type C Type C Type D Type E L-Ascorbic acid B type + acid Type C C type + acid Type D Type E N,N-Bis[(R)-(−)-1-phenylethyl]aminomethylbenzoic acid Type B Type C Type C Type D E type + acid (S)-Phenylsuccinic acid Type B Type C C type + acid Type D E type + acid ⁺ indicates the crystal form of free racemic-dione (no cocrystal formed), *: (1S)-(−)-camphoric acid cocrystal, ^# : (+)-2,3-dibenzoyl-D-tartaric acid cocrystal, ^$ : D-(+)-apple acid cocrystal [ Table 2-2 ] Summary of HPLC data of three cocrystals Peak area samples Supernatant Solid p-Diketone (area) Meta-diketone (area) M/P p-Diketone (area) Meta-diketone (area) M/P (1S)-(-)-Camphoric acid cocrystal form A (810465-06-C3) 9021.4 8274.2 0.9 6418.6 6360.4 1.0 (1S)-(-)-Camphoric acid cocrystal form B (810465-06-D3) 4673.2 4303.4 0.9 4768.3 4736.9 1.0 DBTA eutectic type A (810465-06-D5) 17673.1 1858.6 0.11 1180.2 5249.8 4.4 D-(+)-Apple acid cocrystal form A (810465-06-C7) 11382.6 10696.5 0.9 6443.3 6366.7 1.0 2.2 Solvent Screening

為了選擇適合的溶劑以進一步拆分間二酮及對二酮，收集間/對-二酮在20多種溶劑/溶劑混合物中的HPLC的面積比。如表2-3所列，2-MeTHF顯示出最佳拆分，其中間二酮/對二酮面積比在上清液中為0.7，並且在殘留固體中為4.1。然而，2-MeTHF/正庚烷（1:1，v/v）在共晶體篩選過程中顯示出更好的拆分結果（表2-2），因此選擇了2-MeTHF/正庚烷進行進一步優化。以不同比率的2-MeTHF/正庚烷用不同的酸/鹼比收集間/對-二酮的HPLC的面積比。表2-4中的結果顯示，在2-MeTHF/正庚烷（8:1或4:1，v/v）中需要更高的酸/FB（2:1或1.5:1）的比率以提高分離固體中的間/對-二酮的比率。In order to select a suitable solvent for further resolution of m-dione and p-dione, the HPLC area ratios of m-dione/p-dione in more than 20 solvents/solvent mixtures were collected. As listed in Table 2-3, 2-MeTHF showed the best resolution, with a m-dione/p-dione area ratio of 0.7 in the supernatant and 4.1 in the residual solid. However, 2-MeTHF/n-heptane (1:1, v/v) showed better resolution results in the co-crystal screening process (Table 2-2), so 2-MeTHF/n-heptane was selected for further optimization. The HPLC area ratios of m-dione/p-dione were collected with different acid/base ratios in different ratios of 2-MeTHF/n-heptane. The results in Tables 2-4 show that a higher acid/FB ratio (2:1 or 1.5:1) is required in 2-MeTHF/n-heptane (8:1 or 4:1, v/v) to increase the ratio of m/p-dione in the isolated solid.

間共晶體及對共晶體在不同比率的2-MeTHF/正庚烷中的溶解度亦在5℃及25℃下進行，這總結於表2-5中。客戶提供間共晶體，並藉由反向反溶劑（reverse anti-solvent）及反溶劑製備對共晶體（實驗細節參見第4.3部分）。表2-5中的溶解度結果顯示，2-MeTHF/正庚烷的體積比為1.5:1，可以在室溫下得到最佳拆分。客戶進行了更多的拆分實驗，其中1.4:1的體積比顯示最佳拆分結果。因此，選擇1.4:1的2-MeTHF/正庚烷的體積比作為溶劑系統用於拆分。 [表 2-3 ]二酮外消旋物 DBTA 共晶體的溶劑篩選 （間二酮 / 對二酮面積比） 溶劑 上清液 固體溶劑 上清液 固體 2-MeTHF 0.7 4.1 DMSO/正庚烷（1 : 1，v/v） NA NA MTBE 0.04 3.5 DMF/正庚烷（1 : 1，v/v） 0.9 1.0 MeOH 0.9 1.0 甲苯/正庚烷（1 : 1，v/v） 0.8 1.0 IPA 1.0 1.0 乙酸 NA NA EtOH/正庚烷（1 : 1，v/v） 0.9 1.0 甲酸 NA NA MIBK 0.9 1.0 DCM NA NA MEK 1.0 1.0 異丙苯 0.9 1.0 IPAc 0.9 1.0 1-丁醇 0.9 1.0 THF NA NA 正丙醇 0.9 1.0 NMP NA NA 1,3-二甲基-2-咪唑啉酮 0.9 1.0 NA: 獲得澄清溶液，並且沒有分離出固體。 [表 2-4 ]用二酮外消旋物 DBTA 共晶體篩選酸 / 鹼比及 2-MeTHF/ 正庚烷比的結果（間二酮 / 對二酮面積比） 酸 / 鹼比 2-MeTHF / 正庚烷（v/v ） 2:1 1.5:1 1:1.5 1:2 形式 L S 形式 L S 形式 L S 形式 L S 8 : 1 CA 0.4 13.4 CA 0.4 8.9 CA 0.5 7.0 CA 0.6 2.6 4 : 1 CA 0.3 8.7 CA 0.3 6.2 CA 0.4 6.2 CA 0.4 5.7 2 : 1 CA 0.2 6.0 CA 0.2 5.6 CA 0.2 4.7 CA 0.2 5.2 1 : 2 CA 0.3 1.2 CA 0.1 1.3 CA 0.1 1.4 CA 0.1 1.7 1 : 4 DA 1.4 1.0 CA 0.4 1.0 CA+ DA 0.1 1.0 CA 0.1 1.0 1 : 8 CA+ DA 0.9 1.0 DA 0.5 1.0 DA 0.3 1.0 DA 0.3 1.0 L: 上清液，S：固體，CA：A型共晶體，DA：A型二酮外消旋物 [表 2-5 ]間 / 對 - 二酮共晶體的 2-MeTHF/ 正庚烷比篩選 溫度（ ℃ ） 2-MeTHF/ 正庚烷（ v/v ） 間二酮共晶體 對二酮共晶體 溶解度（mg/mL） XRPD 溶解度（mg/mL） XRPD 5 1:1 11.3 A*型 38.5 A^# 型 1.5:1 17.3 A*型 60.8 A^# 型 2:1 22.2 A*型 66.9 A^# 型 3:1 28.6 A*型 86.6 A^# 型 4:1 30.8 A*型 82.9 A^# 型 6:1 47.1 A*型 92.1 NA 8:1 55.1 A*型 90.6 NA 25 1:1 13.4 A*型 52.9 A^# 型 1.5:1 20.3 A*型 80.8 A^# 型 2:1 28.1 A*型 81.7 A^# 型 3:1 39.0 A*型 87.0 NA 4:1 43.0 A*型 86.5 NA 6:1 53.2 A*型 81.9 NA 8:1 65.0 A*型 89.2 NA *：A型間共晶體，^# ：A型對共晶體2.3 二酮 DBTA 共晶體，二酮外消旋物及 DBTA 的溶解度 The solubility of the meta-cocrystal and the para-cocrystal in different ratios of 2-MeTHF/n-heptane was also conducted at 5°C and 25°C, which is summarized in Table 2-5. The client provided the meta-cocrystal and the para-cocrystal was prepared by reverse anti-solvent and anti-solvent (see Section 4.3 for experimental details). The solubility results in Table 2-5 show that a volume ratio of 2-MeTHF/n-heptane of 1.5:1 can obtain the best resolution at room temperature. The client conducted more resolution experiments, in which a volume ratio of 1.4:1 showed the best resolution results. Therefore, a volume ratio of 2-MeTHF/n-heptane of 1.4:1 was selected as the solvent system for resolution. [ Table 2-3 ] Solvent screening of diketone racemate DBTA cocrystals (meta-diketone / para-diketone area ratio) Solvent Supernatant Solid Solvent Supernatant Solid 2-MeTHF 0.7 4.1 DMSO/n-heptane (1:1, v/v) NA NA MTBE 0.04 3.5 DMF/n-heptane (1:1, v/v) 0.9 1.0 MeOH 0.9 1.0 Toluene/n-heptane (1:1, v/v) 0.8 1.0 IPA 1.0 1.0 Acetic acid NA NA EtOH/n-heptane (1:1, v/v) 0.9 1.0 Formic acid NA NA MIBK 0.9 1.0 DCM NA NA MEK 1.0 1.0 Cumene 0.9 1.0 IPA 0.9 1.0 1-Butanol 0.9 1.0 THF NA NA n-Propanol 0.9 1.0 NMP NA NA 1,3-Dimethyl-2-imidazolidinone 0.9 1.0 NA: A clear solution was obtained and no solid was isolated. [ Table 2-4 ] Results of screening the acid / base ratio and 2-MeTHF/ n-heptane ratio using the diketone racemate DBTA cocrystal (meta-diketone / para-diketone area ratio) Acid / base ratio 2-MeTHF/ n-heptane (v/v ) 2:1 1.5:1 1:1.5 1:2 form L S form L S form L S form L S 8 : 1 CA 0.4 13.4 CA 0.4 8.9 CA 0.5 7.0 CA 0.6 2.6 4 : 1 CA 0.3 8.7 CA 0.3 6.2 CA 0.4 6.2 CA 0.4 5.7 twenty one CA 0.2 6.0 CA 0.2 5.6 CA 0.2 4.7 CA 0.2 5.2 1 : 2 CA 0.3 1.2 CA 0.1 1.3 CA 0.1 1.4 CA 0.1 1.7 1 : 4 DA 1.4 1.0 CA 0.4 1.0 CA+DA 0.1 1.0 CA 0.1 1.0 1 : 8 CA+DA 0.9 1.0 DA 0.5 1.0 DA 0.3 1.0 DA 0.3 1.0 L: supernatant, S: solid, CA: A-type cocrystal, DA: A-type diketone racemate [ Table 2-5 ] 2-MeTHF/ n - heptane ratio screening of m/ p - diketone cocrystals Temperature ( ℃ ) 2-MeTHF/ n-heptane ( v/v ) Meta-diketone cocrystal p-Diketone cocrystal Solubility (mg/mL) XRPD Solubility (mg/mL) XRPD 5 1:1 11.3 Type A* 38.5 Type A ^# 1.5:1 17.3 Type A* 60.8 Type A ^# 2:1 22.2 Type A* 66.9 Type A ^# 3:1 28.6 Type A* 86.6 Type A ^# 4:1 30.8 Type A* 82.9 Type A ^# 6:1 47.1 Type A* 92.1 NA 8:1 55.1 Type A* 90.6 NA 25 1:1 13.4 Type A* 52.9 Type A ^# 1.5:1 20.3 Type A* 80.8 Type A ^# 2:1 28.1 Type A* 81.7 Type A ^# 3:1 39.0 Type A* 87.0 NA 4:1 43.0 Type A* 86.5 NA 6:1 53.2 Type A* 81.9 NA 8:1 65.0 Type A* 89.2 NA *: A-type inter-cocrystal, ^# : A-type para-cocrystal 2.3 Solubility of diketone DBTA cocrystal, diketone racemate and DBTA

在不同溫度（20℃、30℃、40℃、50℃、60℃、65℃、75℃及80℃）下，在2-MeTHF/正庚烷（1.4:1，v/v）中建立間二酮共晶體、對二酮共晶體、間+對二酮共晶體混合物（1:1，w/w）及二酮外消旋物的7天平衡溶解度。5天後在75℃及80℃下觀察到顏色變化，表明降解，因此未收集到溶解度。Seven-day equilibrium solubility of the meta-diketone cocrystals, para-diketone cocrystals, meta+para-diketone cocrystal mixture (1:1, w/w), and diketone racemate was established in 2-MeTHF/n-heptane (1.4:1, v/v) at different temperatures (20°C, 30°C, 40°C, 50°C, 60°C, 65°C, 75°C, and 80°C). Color changes were observed after 5 days at 75°C and 80°C, indicating degradation, so no solubility was collected.

在不同溫度下將間共晶體及對共晶體攪拌7天時，未觀察到形式變化（圖2-5及圖2-6）。在不同溫度下將間二酮共晶體及對二酮共晶體混合物（1:1，w/w）的混合物攪拌7天後，獲得C型二酮外消旋物（圖2-7）。在不同溫度下攪拌二酮外消旋物7天後，觀察到D型二酮外消旋物（20℃及30℃）及C型二酮外消旋物（40℃、50℃、60℃及65℃）（圖2-8及圖2-9）。When the meta-cocrystal and para-cocrystal were stirred at different temperatures for 7 days, no form change was observed (Figure 2-5 and Figure 2-6). After the mixture of the meta-diketone cocrystal and the para-diketone cocrystal mixture (1:1, w/w) was stirred at different temperatures for 7 days, the C-type diketone racemate was obtained (Figure 2-7). After the diketone racemate was stirred at different temperatures for 7 days, the D-type diketone racemate (20℃ and 30℃) and the C-type diketone racemate (40℃, 50℃, 60℃ and 65℃) were observed (Figure 2-8 and Figure 2-9).

在不同溫度（20℃、30℃、40℃、50℃、60℃及65℃）下在2-MeTHF/正庚烷（1.4:1，v/v）中建立DBTA的5天平衡溶解度。在所有溫度下均觀察到約100 mg/mL的溶解度。在不同溫度下均未觀察到顯著差異（表2-7）。 [表 2-6 ]二酮 DBTA 共晶體、間 / 對 - 二酮共晶體的混合物、二酮外消旋物在 2-MeTHF/ 正庚烷（ 1.4 : 1 ， v/v ）中的溶解度 樣本 ID 材料 溫度（ ℃ ） 溶解度（ mg/mL ） 晶體形式 間二酮 對二酮 1-01-A1 間二酮共晶體 20 13.1 - A型間共晶體 1-01-A2 30 15.8 - A型間共晶體 1-01-A3 40 18.4 - A型間共晶體 1-01-A4 50 17.2 - A型間共晶體 1-01-A5 60 34.6 - A型間共晶體 1-01-A6 65 35.4 - A型間共晶體 1-01-B1 對二酮, 共晶體 20 - 39.4 A型對共晶體 1-01-B2 30 - 56.5 A型對共晶體 1-01-B3 40 - 55.8 A型對共晶體 1-01-B4 50 - 79.9 A型對共晶體 1-01-B5 60 - 113.9 A型對共晶體 1-01-B6 65 - 110.0 A型對共晶體 1-01-C1 間+對二酮共晶體混合物 20 7.3 10.4 C型二酮外消旋物 1-01-C2 30 9.2 16.0 C型二酮外消旋物 1-01-C3 40 9.8 12.2 C型二酮外消旋物 1-01-C4 50 12.1 21.9 C型二酮外消旋物 1-01-C5 60 18.7 26.7 C型二酮外消旋物 1-01-C6 65 13.4* 18.0* C型二酮外消旋物 1-01-D1 二酮外消旋物 20 18.0 15.2 D型二酮外消旋物 1-01-D2 30 20.1 17.1 D型二酮外消旋物 1-01-D3 40 11.5 9.9 C型二酮外消旋物 1-01-D4 50 14.2 11.8 C型二酮外消旋物 1-01-D5 60 13.7 11.7 C型二酮外消旋物 1-01-D6 65 15.3 13.1 C型二酮外消旋物 [表 2-7 ]DBTA 在 2-MeTHF/ 正庚烷（ 1.4:1, v/v ）中的溶解度 樣本 ID 溫度（ ℃ ） 溶解度（ mg/mL ） 1-15-A1 20 99.1 1-15-A2 30 100.3 1-15-A3 40 98.9 1-15-A4 50 88.0 1-15-A5 60 105.0 1-15-A6 65 96.1 2.4 三元相圖 2.4.1 間 / 對 - 二酮共晶體 The 5-day equilibrium solubility of DBTA was established in 2-MeTHF/n-heptane (1.4:1, v/v) at different temperatures (20°C, 30°C, 40°C, 50°C, 60°C, and 65°C). A solubility of approximately 100 mg/mL was observed at all temperatures. No significant differences were observed at different temperatures (Table 2-7). [ Table 2-6 ] Solubility of diketone DBTA cocrystals, mixtures of meta / para - diketone cocrystals, and diketone racemates in 2-MeTHF/ n-heptane ( 1.4:1 , v/v ) Sample ID Material Temperature ( ℃ ) Solubility ( mg/mL ) Crystalline form Meta-diketone p-Diketone 1-01-A1 Meta-diketone cocrystal 20 13.1 - A-type eutectic 1-01-A2 30 15.8 - A-type eutectic 1-01-A3 40 18.4 - A-type eutectic 1-01-A4 50 17.2 - A-type eutectic 1-01-A5 60 34.6 - A-type eutectic 1-01-A6 65 35.4 - A-type eutectic 1-01-B1 p-Diketone, Cocrystal 20 - 39.4 A-type eutectic 1-01-B2 30 - 56.5 A-type eutectic 1-01-B3 40 - 55.8 A-type eutectic 1-01-B4 50 - 79.9 A-type eutectic 1-01-B5 60 - 113.9 A-type eutectic 1-01-B6 65 - 110.0 A-type eutectic 1-01-C1 m+p-diketone eutectic mixture 20 7.3 10.4 C-type diketone racemate 1-01-C2 30 9.2 16.0 C-type diketone racemate 1-01-C3 40 9.8 12.2 C-type diketone racemate 1-01-C4 50 12.1 21.9 C-type diketone racemate 1-01-C5 60 18.7 26.7 C-type diketone racemate 1-01-C6 65 13.4* 18.0* C-type diketone racemate 1-01-D1 Diketone racemate 20 18.0 15.2 D-diketone racemate 1-01-D2 30 20.1 17.1 D-diketone racemate 1-01-D3 40 11.5 9.9 C-type diketone racemate 1-01-D4 50 14.2 11.8 C-type diketone racemate 1-01-D5 60 13.7 11.7 C-type diketone racemate 1-01-D6 65 15.3 13.1 C-type diketone racemate [ Table 2-7 ] Solubility of DBTA in 2-MeTHF/ n-heptane ( 1.4:1, v/v ) Sample ID Temperature ( ℃ ) Solubility ( mg/mL ) 1-15-A1 20 99.1 1-15-A2 30 100.3 1-15-A3 40 98.9 1-15-A4 50 88.0 1-15-A5 60 105.0 1-15-A6 65 96.1 2.4 Ternary phase diagram 2.4.1 m / p - diketone eutectic

稱重間二酮共晶體及對二酮共晶體，相應質量列在表2-8中，並在室溫下在2-MeTHF/正庚烷（1.4:1，v/v）中攪拌72小時。基於72小時的平衡溶解度資料繪製了間/對-二酮共晶體之三元相圖，並且未獲得共晶點（圖2-10）。 [表 2-8 ]間 / 對 - 二酮共晶體的溶解度資料總結 # 間共晶體的重量（ mg ） 對共晶體的重量（ mg ） de （ % ） 上清液 固體 [ 間 ] mg/mL [ 對 ] mg/mL de （ % ） [ 間 ]/[ 對 ] 間 mg 對 mg de （ % ） 1 50.7 0 100.0 22.9 0.0 100.0 NA 27.8 0.0 100.0 2 0 99.7 -100.0 0.0 81.2 -100.0 NA 0.0 18.5 -100.0 3 21.1 83.4 -59.6 5.1 59.4 -84.2 11.680 16.0 24.0 -20.0 4 41 83.5 -34.1 5.9 45.0 -76.9 7.658 35.1 38.5 -4.6 5 84 85 -0.6 11.5 23.7 -34.9 2.070 72.5 61.3 8.4 6 167.7 83.1 33.7 12.2 20.8 -26.2 1.711 155.5 62.3 42.8 7 49.7 50.4 -0.7 17.5 40.8 -40.0 2.331 32.2 9.6 54.1 8 49.7 25 33.1 19.9 21.8 -4.6 1.095 29.8 3.2 80.7 9 49.2 12.2 60.3 21.3 9.6 37.9 0.451 27.9 2.6 82.9 2.4.2 間 / 對 - 二酮 The meta-diketone eutectic and para-diketone eutectic were weighed and the corresponding masses are listed in Table 2-8, and stirred in 2-MeTHF/n-heptane (1.4:1, v/v) at room temperature for 72 hours. The ternary phase diagram of the meta-/para-diketone eutectic was drawn based on the equilibrium solubility data for 72 hours, and no eutectic point was obtained (Figure 2-10). [ Table 2-8 ] Summary of solubility data of meta- / para - diketone eutectic # Weight of eutectic ( mg ) Weight of eutectic ( mg ) de （ % ） Supernatant Solid [ Interval ] mg/mL [ Yes ] mg/mL de （ % ） [ Room ]/[ Pair ] mg mg de （ % ） 1 50.7 0 100.0 22.9 0.0 100.0 NA 27.8 0.0 100.0 2 0 99.7 -100.0 0.0 81.2 -100.0 NA 0.0 18.5 -100.0 3 21.1 83.4 -59.6 5.1 59.4 -84.2 11.680 16.0 24.0 -20.0 4 41 83.5 -34.1 5.9 45.0 -76.9 7.658 35.1 38.5 -4.6 5 84 85 -0.6 11.5 23.7 -34.9 2.070 72.5 61.3 8.4 6 167.7 83.1 33.7 12.2 20.8 -26.2 1.711 155.5 62.3 42.8 7 49.7 50.4 -0.7 17.5 40.8 -40.0 2.331 32.2 9.6 54.1 8 49.7 25 33.1 19.9 21.8 -4.6 1.095 29.8 3.2 80.7 9 49.2 12.2 60.3 21.3 9.6 37.9 0.451 27.9 2.6 82.9 2.4.2 m / p - dione

稱重間二酮及對二酮，相應質量列在表2-9中，並在室溫下在2-MeTHF/正庚烷（1.4:1，v/v）中攪拌5天。基於在室溫下在1.0 mL 2-MeTHF/正庚烷（1.4:1，v/v）中的5天平衡溶解度資料繪製三元相圖。在溶解度樣本的殘留固體中觀察到A型間二酮、A型對二酮、C型及D型二酮外消旋物。相圖中未獲得共晶點（圖2-11）。 [表 2-9 ]間 / 對 - 二酮之三元相圖的資料總結 # 間二酮的重量（ mg ） 對二酮的重量（ mg ） de （ % ） 上清液 固體 XRPD [ 間 ] mg/mL [ 對 ] mg/mL de （ % ） [ 間 ]/[ 對 ] 間 mg 對 mg de （ % ） 1 99.3 0 100.0 80.1 0 100.0 NA 19.2 0.0 100.0 A 2 0 100.6 -100.0 0 77.1 -100.0 NA 0.0 23.5 -100.0 A 3 20.2 119.3 -71.0 7.7 50.3 -73.6 0.2 12.5 69.0 -69.2 A+RD 4 89.8 90.3 -0.3 16.2 17.5 -3.9 0.9 73.6 72.8 0.6 RD 5 121.1 40.7 49.7 53.0 1.6 94.2 33.4 68.1 39.1 27.0 A+RC 6 90.2 19.5 64.4 52.6 1.4 94.8 37.6 37.6 18.1 35.0 A+RC 7 41.6 39.9 2.1 9.8 9.0 4.4 1.1 31.8 30.9 1.4 RC 8 39.2 120.3 -50.8 7.6 48.1 -72.8 0.2 31.6 72.2 -39.1 A+RD 9 119.1 20.5 70.6 54.1 1.6 94.4 34.5 65.0 18.9 54.9 A+RC RC：C型二酮外消旋物；RD：D型二酮外消旋物；A：A型間或對二酮（A型間二酮及A型對二酮的XRPD圖相同且不可區分）。3 晶體形式的固態表徵 The meta-diketone and para-diketone were weighed and the corresponding masses are listed in Table 2-9, and stirred in 2-MeTHF/n-heptane (1.4:1, v/v) at room temperature for 5 days. A ternary phase diagram was plotted based on the 5-day equilibrium solubility data in 1.0 mL 2-MeTHF/n-heptane (1.4:1, v/v) at room temperature. Type A meta-diketone, type A para-diketone, type C and type D diketone racemates were observed in the residual solid of the solubility sample. No eutectic point was obtained in the phase diagram (Figure 2-11). [ Table 2-9 ] Data summary of the ternary phase diagram of meta- / para - diketones # Weight of diketone ( mg ) Weight of diketone ( mg ) de （ % ） Supernatant Solid XRPD [ Interval ] mg/mL [ Yes ] mg/mL de （ % ） [ Room ]/[ Pair ] mg mg de （ % ） 1 99.3 0 100.0 80.1 0 100.0 NA 19.2 0.0 100.0 A 2 0 100.6 -100.0 0 77.1 -100.0 NA 0.0 23.5 -100.0 A 3 20.2 119.3 -71.0 7.7 50.3 -73.6 0.2 12.5 69.0 -69.2 A+RD 4 89.8 90.3 -0.3 16.2 17.5 -3.9 0.9 73.6 72.8 0.6 RD 5 121.1 40.7 49.7 53.0 1.6 94.2 33.4 68.1 39.1 27.0 A+RC 6 90.2 19.5 64.4 52.6 1.4 94.8 37.6 37.6 18.1 35.0 A+RC 7 41.6 39.9 2.1 9.8 9.0 4.4 1.1 31.8 30.9 1.4 RC 8 39.2 120.3 -50.8 7.6 48.1 -72.8 0.2 31.6 72.2 -39.1 A+RD 9 119.1 20.5 70.6 54.1 1.6 94.4 34.5 65.0 18.9 54.9 A+RC RC: C-type dione racemate; RD: D-type dione racemate; A: A-type meta-diketone (the XRPD patterns of A-type meta-diketone and A-type para-diketone are identical and indistinguishable). 3 Solid-state characterization of crystalline forms

總共獲得了五種二酮外消旋物晶體形式及兩種共晶體形式。所有該等形式均藉由XRPD、TGA、DSC、PLM及¹ H NMR表徵，並且總結在表2-10中。固態表徵資料表明，將A型及D型二酮外消旋物鑒定為2-MeTHF溶劑化物，將B型鑒定為丙酮溶劑化物，將C型鑒定為無水物，並且將E型鑒定為MTBE溶劑化物。A total of five diketone racemate crystal forms and two co-crystal forms were obtained. All of these forms were characterized by XRPD, TGA, DSC, PLM and ¹ H NMR and are summarized in Table 2-10. The solid state characterization data showed that the diketone racemates A and D were identified as 2-MeTHF solvates, the B type was identified as an acetone solvate, the C type was identified as an anhydrous form, and the E type was identified as an MTBE solvate.

發現A型間二酮共晶體及A型對二酮共晶體均為2-MeTHF溶劑化物。所有表徵資料均展示在圖3-1至圖3-22中。 [表 2-10 ]晶體形式的總結 樣本 ID 晶體形式 吸熱 （峰， ℃ ） TGA （ wt% ） ¹ H NMR （ wt% ） 5-05-A A型二酮外消旋物 110.2, 248.6, 213.4* 2.5（150 ℃） 2.4（2-MeTHF） 1-10-A1 B型二酮外消旋物 113.4, 126.0, 250.9 9.8（150 ℃） 6.2（丙酮） 1-01-D5 C型二酮外消旋物 251.9 3.0（150 ℃） ND^& 1-01-D1 D型二酮外消旋物 120.5, 253.3 15.4（150 ℃） 12.0（2-MeTHF） 1-10-A4 E型二酮外消旋物 151.6, 158.6, 248.7 14.7（160 ℃） 7.5（MTBE） 5-17-A A型間二酮共晶體 109.6, 119.2 6.6（125 ℃） 10.6（2-MeTHF） 5-16-A A型對二酮共晶體 88.3, 112.3, 132.8 9.2（140 ℃） 10.6（2-MeTHF） *：放熱峰；&：未偵測到。3.1.1 二酮外消旋物形式的競爭性漿液 It was found that both the A-type meta-diketone cocrystal and the A-type para-diketone cocrystal were 2-MeTHF solvates. All characterization data are shown in Figures 3-1 to 3-22. [ Table 2-10 ] Summary of crystal forms Sample ID Crystalline form Endothermic (peak, ℃ ) TGA ( wt% ) ¹ H NMR ( wt% ) 5-05-A Diketone racemate type A 110.2, 248.6, 213.4* 2.5 (150°C) 2.4 (2-MeTHF) 1-10-A1 Diketone racemate type B 113.4, 126.0, 250.9 9.8 (150°C) 6.2 (Acetone) 1-01-D5 C-type diketone racemate 251.9 3.0 (150°C) ND ^& 1-01-D1 D-diketone racemate 120.5, 253.3 15.4 (150°C) 12.0 (2-MeTHF) 1-10-A4 E-type diketone racemate 151.6, 158.6, 248.7 14.7 (160°C) 7.5 (MTBE) 5-17-A Type A diketone cocrystal 109.6, 119.2 6.6 (125°C) 10.6 (2-MeTHF) 5-16-A A-type p-diketone cocrystal 88.3, 112.3, 132.8 9.2 (140°C) 10.6 (2-MeTHF) *: exothermic peak; &: not detected. 3.1.1 Competitive slurry in the form of diketone racemate

在室溫下藉由A型二酮外消旋物在丙酮、H₂ O/ACN（1:1，v/v）、2-MeTHF/正庚烷（1.4:1，v/v）及MTBE/正庚烷（1:1，v/v）中的漿液分別成功地再現了B~E型二酮外消旋物。The B~E diketone racemates were successfully reconstituted from slurries of the A diketone racemate in acetone, _H2O /ACN (1:1, v/v), 2-MeTHF/n-heptane (1.4:1, v/v), and MTBE/n-heptane (1:1, v/v) at room temperature, respectively.

將約5 mg每種二酮外消旋物形式（A〜E型）稱重到HPLC小瓶中，將0.3 mL二酮外消旋物在2-MeHTF/正庚烷（1.4:1，v/v）中的飽和溶液添加到小瓶中，並且然後將混合物在20℃、30℃、40℃、50℃、60℃及65℃下攪拌5天。Approximately 5 mg of each dione racemate form (Forms A to E) was weighed into an HPLC vial, 0.3 mL of a saturated solution of the dione racemate in 2-MeHTF/n-heptane (1.4:1, v/v) was added to the vial, and the mixture was then stirred at 20°C, 30°C, 40°C, 50°C, 60°C, and 65°C for 5 days.

所有游離鹼形式均在目標溫度下藉由在2-MeHTF/正庚烷（1.4:1，v/v）中的競爭性漿液轉化為C型二酮外消旋物，這表明C型二酮外消旋物在2-MeHTF/正庚烷（1.4:1，v/v）中在20℃至65℃下是熱力學最穩定形式。 [表 2-11 ]競爭性漿液結果 起始形式 實驗 ID 溶劑 溫度（ ℃ ） 固體形式 A〜E型二酮外消旋物 1-16-B1 2-MeTHF/正庚烷（1.4:1, v/v） 20 C型二酮外消旋物 1-16-B2 30 C型二酮外消旋物 1-16-B3 40 C型二酮外消旋物 1-16-B4 50 C型二酮外消旋物 1-16-B5 60 C型二酮外消旋物 1-16-B6 65 C型二酮外消旋物 3.2 對二酮共晶體的製備 3.2.1 小規模 All free base forms were converted to C-diketone racemate by competitive slurry in 2-MeHTF/n-heptane (1.4:1, v/v) at the target temperature, indicating that C-diketone racemate is the most thermodynamically stable form in 2-MeHTF/n-heptane (1.4:1, v/v) at 20°C to 65°C. [ Table 2-11 ] Competitive slurry results Starting form Experiment ID Solvent Temperature ( ℃ ) Solid form A～E type diketone racemate 1-16-B1 2-MeTHF/n-heptane (1.4:1, v/v) 20 C-type diketone racemate 1-16-B2 30 C-type diketone racemate 1-16-B3 40 C-type diketone racemate 1-16-B4 50 C-type diketone racemate 1-16-B5 60 C-type diketone racemate 1-16-B6 65 C-type diketone racemate 3.2 Preparation of diketone cocrystals 3.2.1 Small scale

在65℃下將2 g對二酮及1 g DBTA溶於18 mL 2-MeTHF中，得到幾乎澄清的溶液。經1 h將18 mL庚烷添加到此溶液中。經4 h將溶液冷卻至20℃，並老化過夜。使用吹氣將溶液在室溫下蒸發約1 h，並且獲得淡黃色油狀糊狀物。將另外54 mL庚烷添加到混合物中，伴隨攪拌2 h。將懸浮液過濾。將固體樣本指定為810465-16-A。3.2.2 大規模 2 g of p-diketone and 1 g of DBTA were dissolved in 18 mL of 2-MeTHF at 65 °C to give an almost clear solution. 18 mL of heptane were added to this solution over 1 h. The solution was cooled to 20 °C over 4 h and aged overnight. The solution was evaporated at room temperature for about 1 h using air blowing, and a light yellow oily paste was obtained. Another 54 mL of heptane was added to the mixture, accompanied by stirring for 2 h. The suspension was filtered. The solid sample was designated 810465-16-A. 3.2.2 Large Scale

在65℃下將10 g對二酮及5 g DBTA溶解在100 mL 2-MeTHF中。用0.45μm PTFE過濾器過濾溶液，並且獲得澄清溶液。將澄清溶液逐滴添加至400 mL庚烷的懸浮液中，該懸浮液含有第一次運行所產生的約1 g種子（810465-16-A）。將懸浮液在室溫下保持攪拌5 h，然後分離。產生約10 g對二酮共晶體（810465-20-A），產率為約66%。4 儀器與方法 4.1 XRPD 10 g of p-diketone and 5 g of DBTA were dissolved in 100 mL of 2-MeTHF at 65 °C. The solution was filtered with a 0.45 μm PTFE filter and a clear solution was obtained. The clear solution was added dropwise to a suspension in 400 mL of heptane containing about 1 g of seeds (810465-16-A) produced in the first run. The suspension was kept stirring at room temperature for 5 h and then separated. About 10 g of p-diketone cocrystal (810465-20-A) was produced with a yield of about 66%. 4 Instruments and Methods 4.1 XRPD

對於XRPD分析，在反射模式下使用了PANalytical X射線粉末衍射儀。表4-1中列出了使用的XRPD參數。 [表 4-1 ]XRPD 測試的參數 參數 PANalytical PANalytical PANalytical 模式 Empyrean X’ Pert³ X’ Pert³ X射線波長 Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1強度比：0.50 Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1強度比：0.50 Cu, kα Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1強度比：0.50 X射線管設置 45 kV, 40 mA 45 kV, 40 mA 45 kV, 40 mA 發散狹縫自動 1/8° 固定的1/8° 掃描模式連續連續連續掃描範圍（°2TH） 3°-40° 3°-40° 3°-40° 掃描步進時間（s） 17.8 46.7 18.9 步長（°2TH） 0.0167 0.0263 0.0131 測試時間 5 min 30 s 5 min 04 s 4 min 15 s 4.2 TGA 及 DSC For XRPD analysis, a PANalytical X-ray powder diffractometer was used in reflection mode. The XRPD parameters used are listed in Table 4-1. [ Table 4-1 ] Parameters of XRPD test Parameters PANalytical PANalytical PANalytical model Empyrean X' Pert ³ X' Pert ³ X-ray wavelength Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1 intensity ratio: 0.50 Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1 intensity ratio: 0.50 Cu, kα Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1 intensity ratio: 0.50 X-ray tube settings 45 kV, 40 mA 45 kV, 40 mA 45 kV, 40 mA Divergent Slits Automatic 1/8° Fixed 1/8° Scan Mode Continuous Continuous Continuous Scanning range (°2TH) 3°-40° 3°-40° 3°-40° Scanning step time (s) 17.8 46.7 18.9 Step length (°2TH) 0.0167 0.0263 0.0131 Test time 5 min 30 s 5 min 04 s 4 min 15 s 4.2 TGA and DSC

使用來自TA儀器的TA Discovery 550、Q500及Q5000 TGA收集TGA資料。使用來自TA儀器的Q500、Q5000及Discovery 2500 DSC進行DSC。表4-2中列出了使用的詳細參數。 [表 4-2 ]TGA 及 DSC 測試的參數 參數 TGA DSC 方法上升上升樣本盤鋁，開口鋁，捲曲溫度室溫 – 350 ℃ 25 ℃ - 300 ℃ 加熱速率 10 ℃/min 10 ℃/min 吹掃氣體 N₂ N₂ 4.3 HPLC TGA data were collected using TA Discovery 550, Q500 and Q5000 TGA from TA Instruments. DSC was performed using Q500, Q5000 and Discovery 2500 DSC from TA Instruments. The detailed parameters used are listed in Table 4-2. [ Table 4-2 ] Parameters of TGA and DSC Tests Parameters TGA DSC method rise rise Sample Plate Aluminum, open Aluminum, Curled temperature Room temperature – 350 ℃ 25℃ - 300℃ Heating rate 10 ℃/min 10 ℃/min Purge gas N ₂ N ₂ 4.3 HPLC

利用安捷倫1100/1260 HPLC來測試溶解度，詳細方法列於表4-3中。 [表 4-3 ]用於溶解度測試的 HPLC 方法 HPLC 配備 DAD 偵測器的安捷倫 1100 柱 CHIRALPAK IC-3, 4.6x100 mm, 3 um 流動相 A：正庚烷 B：MeOH/EtOH（1 : 1，v/v） 等度溶離 A:B=75:25, 60:40 執行時間 10.0 min 後執行時間 0.0 min 流速 1.0 mL/min 注射體積 5 µL 偵測器波長 UV 215 nm 柱溫 40 ℃ 取樣器溫度 室溫 稀釋劑 EtOH [表 4-4 ]用於溶解度測試的 HPLC 方法（ DBTA ） HPLC 配備 DAD 偵測器的安捷倫 1260 柱安捷倫ZORBAX 300SB-C3, 150 × 4.6 mm, 3.5 µm 流動相 A：在H₂ O中的0.05% TFA B：在ACN中的0.05% TFA 等度溶離 A:B=65:35 執行時間 5.0 min 後執行時間 0.0 min 流速 0.6 mL/min 注射體積 5 µL 偵測器波長 UV 215 nm 柱溫 40 ℃ 取樣器溫度 室溫 稀釋劑 EtOH 4.4¹ H NMR Agilent 1100/1260 HPLC was used to test the solubility. The detailed method is listed in Table 4-3. [ Table 4-3 ] HPLC method used for solubility test HPLC Agilent 1100 with DAD detector column CHIRALPAK IC-3, 4.6x100 mm, 3 um Mobile phase A: n-heptane B: MeOH/EtOH (1:1, v/v) Isocratic elution A:B=75:25, 60:40 Execution time 10.0 min Post-execution time 0.0 min Flow rate 1.0 mL/min Injection volume 5 µL Detector wavelength UV 215 nm Column temperature 40 ℃ Sampler temperature Room temperature Diluent EtOH [ Table 4-4 ] HPLC method for solubility test ( DBTA ) HPLC Agilent 1260 with DAD detector column Agilent ZORBAX 300SB-C3, 150 × 4.6 mm, 3.5 µm Mobile phase A: 0.05% TFA in _H2O B: 0.05% TFA in ACN Isocratic elution A:B=65:35 Execution time 5.0 min Post-execution time 0.0 min Flow rate 0.6 mL/min Injection volume 5 µL Detector wavelength UV 215 nm Column temperature 40 ℃ Sampler temperature Room temperature Diluent EtOH 4.4 ¹ H NMR

使用DMSO-d ₆ 作為溶劑，在Bruker 400M NMR光譜儀上收集¹ H NMR譜圖。4.5 PLM ¹ H NMR spectra were collected on a Bruker _400M NMR spectrometer using DMSO- d6 as solvent. 4.5 PLM

在室溫下在Nikon DS-Fi2立式顯微鏡上捕獲偏光顯微鏡圖片。用 1,3- 二苯基 -3- 側氧基丙磺酸 11b 另外篩選化合物 5 。 Polarized light microscopy images were captured on a Nikon DS-Fi2 upright microscope at room temperature. Compound 5 was additionally screened with 1,3 -diphenyl - 3-hydroxypropanesulfonic acid 11b .

由於化合物5 中吡啶部分的鹼性低，並且使用標準的篩選設置在形成結晶鹽方面有限的『命中』，因此選擇它來在0.06 mmol規模下用1,3-二苯基-3-側氧基丙磺酸11b篩選外消旋化合物4。 (+)-鏡像異構物 (-)-鏡像異構物 Due to the low basicity of the pyridine moiety in compound 5 and the limited ‘hits’ in forming crystalline salts using the standard screening setup, it was chosen to screen racemic compound 4 with 1,3-diphenyl-3-hydroxypropanesulfonic acid 11b at 0.06 mmol scale. (+)-Mirror image isomer (-)-Mirror image isomer

外消旋化合物5的克級拆分：在250 mL圓底燒瓶中充入在200 mL EtOH:AcOH（90 : 10 v：v））中的2.0 g外消旋化合物4（5.7 mmol，1.0當量）。材料已經溶解後，將832 mg磺酸11b（2.9 mmol，0.5當量）添加到溶液中。將該澄清溶液以800 rpm的攪拌速度攪拌15小時。形成白色沈澱，將其從母液中分離出來。將分離出的鹽懸浮在CH₂ Cl₂ 中，使用分液漏斗用濃NaHCO₃ 水溶液對其進行處理。分離有機層，並將鹼性水層用CH₂ Cl₂ （2x）萃取。合併有機層並經Na₂ SO₃ 乾燥。蒸發溶劑得到415 mg （間）-5（96% ee）（參見圖6-1）。Gram-scale resolution of racemic compound 5: A 250 mL round-bottom flask was charged with 2.0 g of racemic compound 4 (5.7 mmol, 1.0 eq.) in 200 mL of EtOH:AcOH (90:10 v:v). After the material had dissolved, 832 mg of sulfonic acid 11b (2.9 mmol, 0.5 eq.) was added to the solution. The clear solution was stirred at a stirring speed of 800 rpm for 15 h. A white precipitate was formed, which was separated from the mother liquor. The isolated salt was suspended in _CH2Cl2 and treated with concentrated aqueous _NaHCO3 using a separatory _funnel . The organic layer was separated and _the basic aqueous layer was extracted with _CH2Cl2 (2x). The organic layers were combined and dried over Na ₂ SO _3. The solvent was evaporated to give 415 mg of (m)-5 (96% ee) (see Figure 6-1).

將澄清母液蒸發至乾燥。將黃色油狀材料溶解在CH₂ Cl₂ 中，並使用分液漏斗用濃NaHCO₃ 水溶液進行處理。分離有機層，並將鹼性水層用CH₂ Cl₂ （2x）萃取。合併有機層並經Na₂ SO₃ 乾燥。蒸發溶劑得到1579 mg 5（在（對）-阻轉異構物中為23% ee；圖6-2）。間二酮 DBTA 共晶體的多晶型篩選 5 間二酮 DBTA 共晶體的晶體形式的表徵 The clear mother liquor was evaporated to dryness. The yellow oily material was dissolved in CH ₂ Cl ₂ and treated with concentrated aqueous NaHCO ₃ using a separatory funnel. The organic layer was separated and the basic aqueous layer was extracted with CH ₂ Cl ₂ (2x). The organic layers were combined and dried over Na ₂ SO _3. Evaporation of the solvent gave 1579 mg of 5 (23% ee in the (para)-atropisomer; Figure 6-2). Polymorph Screening of Meta-Diketone DBTA Cocrystals Characterization of the Crystalline Form of Meta-Diketone DBTA Cocrystals 5

使用漿液轉化、緩慢蒸發、緩慢冷卻、添加反溶劑、蒸氣擴散、溫度循環及濕磨的方法在100種條件下建立間二酮的多晶型篩選實驗。從篩選共獲得17種晶體形式（A〜Q型）。形式關係如圖4-1所示。表5-1中提供了詳細的表徵資料，並且圖5-1中顯示了XRPD圖的疊加圖。固態表徵結果表明G型係水合物，而其他類型係溶劑化物。5.1 儀器與方法 5.1.1 XRPD A polymorph screening experiment of dione was established under 100 conditions using slurry conversion, slow evaporation, slow cooling, anti-solvent addition, vapor diffusion, temperature cycling and wet milling methods. A total of 17 crystal forms (A~Q forms) were obtained from the screening. The form relationship is shown in Figure 4-1. Detailed characterization data are provided in Table 5-1, and the overlay of the XRPD pattern is shown in Figure 5-1. The solid state characterization results indicate that type G is a hydrate, while the other types are solvates. 5.1 Instruments and methods 5.1.1 XRPD

使用Panalytical X’Pert³ 粉末XRPD在Si零背景支持器上進行XRPD。相對於Panalytical Si參考標準盤校準2θ位置。表5-a中列出了使用的參數。 [表 5-a ]用於 XRPD 測試的參數 參數 反射模式 X射線波長 Cu, kα Kα1 (Å): 1.540598, Kα2 (Å): 1.544426, Kα2/Kα1強度比：0.50 X射線管設置 45 kV, 40 mA 發散狹縫固定的1/8° 掃描模式連續掃描範圍（° 2TH） 3-40 掃描步進時間[s] 18.87 步長（° 2TH） 0.0131 測試時間 4 min 15 s 5.1.2 TGA/DSC XRPD was performed on a Si zero background support using a Panalytical X'Pert ³ powder XRPD. The 2θ position was calibrated relative to a Panalytical Si reference standard disk. The parameters used are listed in Table 5-a. [ Table 5-a ] Parameters used for XRPD testing Parameters Reflection Mode X-ray wavelength Cu, kα Kα1 (Å): 1.540598, Kα2 (Å): 1.544426, Kα2/Kα1 intensity ratio: 0.50 X-ray tube settings 45 kV, 40 mA Divergent Slits Fixed 1/8° Scan Mode Continuous Scanning range (° 2TH) 3-40 Scan step time [s] 18.87 Step length (° 2TH) 0.0131 Test time 4 min 15 s 5.1.2 TGA/DSC

使用來自TA儀器的TA Discovery 550 TGA收集TGA資料。使用來自TA儀器的TA Q2000 DSC進行DSC。DSC用銦參考標準物校準，並且TGA使用鎳參考標準物校準。表5-b中列出了使用的詳細參數。 [表 5-b ]用於 TGA 及 DSC 測試的參數 參數 TGA DSC 方法上升上升樣本盤鉑，開口鋁，捲曲溫度室溫-所需溫度加熱速率 10 ℃/min 吹掃氣體 N₂ 5.2 多晶型篩選 TGA data were collected using a TA Discovery 550 TGA from TA Instruments. DSC was performed using a TA Q2000 DSC from TA Instruments. The DSC was calibrated with indium reference standards and the TGA was calibrated with nickel reference standards. The detailed parameters used are listed in Table 5-b. [ Table 5-b ] Parameters used for TGA and DSC tests Parameters TGA DSC method rise rise Sample Plate Platinum, Open Aluminum, Curled temperature Room temperature - required temperature Heating rate 10 ℃/min Purge gas N ₂ 5.2 Polymorph Screening

在室溫下估計A型（3-05-A）的溶解度。將約2 mg固體添加到3 mL玻璃小瓶中。然後將表5-c中的溶劑逐步（50μL/50μL/200μL/700 μL）添加到小瓶中，直到固體溶解或總體積達到2 mL。表5-c中總結的結果用於在多晶型篩選中指導溶劑選擇。The solubility of Form A (3-05-A) was estimated at room temperature. Approximately 2 mg of solid was added to a 3 mL glass vial. The solvents in Table 5-c were then added to the vial stepwise (50 μL/50 μL/200 μL/700 μL) until the solid dissolved or the total volume reached 2 mL. The results summarized in Table 5-c were used to guide solvent selection in polymorph screening.

使用不同的結晶或固體轉變方法進行多晶型篩選實驗。表5-c中總結了所利用的方法及所鑒定的晶型。 [表 5-c ]起始材料（ 6010013-05-A ）在室溫下的近似溶解度 溶劑 溶解度（ mg/mL ）溶劑 溶解度（ mg/mL ） MTBE S ＜ 3.1 丙酮 S ＞ 52.0 H₂ O 2.4 ＜ S ＜ 8.0 DMF S ＞ 40.0 正庚烷 3.0 ＜ S ＜ 10.0 苯甲醚 S ＞ 40.0 甲苯 2.7 ＜ S ＜ 9.0 乙酸 S ＞ 40.0 己烷 2.9 ＜ S ＜ 9.7 THF S ＞ 50.0 IPA 26.0 ＜ S ＜ 52.0 ACN S ＞ 46.0 2-MeTHF 24.0 ＜ S ＜ 48.0 CHCl3 S ＞ 50.0 1,4-二噁烷 25.0 ＜ S ＜ 50.0 EtOAc S ＞ 72.0 n-BuOH 23.0 ＜ S ＜ 46.0 DMSO S ＞ 72.0 MIBK 38.0 ＜ S ＜ 76.0 MeOH S ＞ 78.0 BuOAc S ＞ 28.0 EtOH S ＞ 68.0 IPAc S ＞ 32.0 -- -- [表 5-d ]多晶型篩選實驗總結 方法 實驗的編號 晶型在室溫/5℃下的漿液 37 A ~ G型、J型、N型、N型緩慢蒸發 16 A型、C型、D型、J型、K型、L型、N型、O型緩慢冷卻 9 C型、J型、L型、O型反溶劑添加 9 A型、C型、H型及I型液體蒸氣擴散 5 L型、M型、Q型固體蒸氣擴散 6 A型及M型溫度循環 7 A型、G型、O型濕磨 10 A型總計 99 A~Q型 5.2.1 室溫下的漿液 Polymorph screening experiments were performed using different crystallization or solid state transformation methods. The methods used and the polymorphs identified are summarized in Table 5-c. [ Table 5-c ] Approximate solubility of the starting material ( 6010013-05-A ) at room temperature Solvent Solubility ( mg/mL ) Solvent Solubility ( mg/mL ) MTBE S ＜ 3.1 acetone S ＞ 52.0 _H2O 2.4 ＜ S ＜ 8.0 DMF S ＞ 40.0 n-Heptane 3.0 ＜ S ＜ 10.0 Anisole S ＞ 40.0 Toluene 2.7 ＜ S ＜ 9.0 Acetic acid S ＞ 40.0 Hexane 2.9 ＜ S ＜ 9.7 THF S ＞ 50.0 IPA 26.0 ＜ S ＜ 52.0 ACN S ＞ 46.0 2-MeTHF 24.0 ＜ S ＜ 48.0 CHCl3 S ＞ 50.0 1,4-Dioxane 25.0 ＜ S ＜ 50.0 EtOAc S ＞ 72.0 n-BuOH 23.0 ＜ S ＜ 46.0 DMSO S ＞ 72.0 MIBK 38.0 ＜ S ＜ 76.0 MeOH S ＞ 78.0 B O S ＞ 28.0 EtOH S ＞ 68.0 IPA S ＞ 32.0 -- -- [ Table 5-d ] Summary of polymorph screening experiments method Experiment ID Crystal form Slurry at room temperature/5°C 37 A ~ G type, J type, N type, N type Slow evaporation 16 Type A, Type C, Type D, Type J, Type K, Type L, Type N, Type O Slow cooling 9 C type, J type, L type, O type Antisolvent addition 9 Type A, Type C, Type H and Type I Liquid vapor diffusion 5 L-type, M-type, Q-type Solid vapor diffusion 6 Type A and Type M Temperature cycle 7 Type A, Type G, Type O Wet grinding 10 Type A Total 99 A~Q type 5.2.1 Slurry at room temperature

在室溫下在不同的溶劑系統中進行漿液實驗。將約20 mg A型（3-05-A）懸浮在3-mL玻璃小瓶中的0.2 mL溶劑中。在室溫下將懸浮液磁力攪拌13天後，分離出剩餘的固體用於XRPD分析。表5-e中總結的結果表明獲得了A〜D型及J型。 [表5-e ]室溫下漿液實驗的總結 實驗 ID 溶劑（ v : v ） 固體形式 3-07-A1 MTBE B型 3-07-A2 H₂ O A型 3-07-A3 正庚烷低結晶度 3-07-A4 甲苯低結晶度 3-07-A5 己烷 A型 3-07-A6* IPA A型 3-07-A7* 2-MeTHF B型 3-07-A8* 1,4-二噁烷 J型 3-07-A9 n-BuOH 低結晶度 3-07-A10* MIBK A型 3-07-A11 BuOAc C型 3-07-A12 IPAc D型 3-07-A13* 丙酮非晶形 3-07-A14* DMF P型 3-07-A15 苯甲醚 E型 3-07-A16 THF/正庚烷（1：9）低結晶度 3-07-A17 2-MeTHF/正庚烷（1：9） A型 3-07-A18 IPA/H2O（1：9） A型 3-07-A19 IPAc/H2O（1：9） F型 3-07-A20 n-BuOH/H2O（1：9） A型 3-07-A21 n-BuOH/MTBE（1：9） A型 3-07-A22 CHCl3/MTBE（1：9） A型 3-07-A23* MeOH/H2O （937：63, aw=0.2）非晶形 3-07-A24* MeOH/H2O （844：156, aw=0.4） N型 3-07-A25* MeOH/H2O （693：304, aw=0.6） G型 3-07-A26 MeOH/H2O （569：431, aw=0.8） G型 *：室溫下藉由緩慢蒸發獲得的固體5.2.2 緩慢蒸發 Slurry experiments were performed at room temperature in different solvent systems. About 20 mg of Form A (3-05-A) was suspended in 0.2 mL of solvent in a 3-mL glass vial. After the suspension was magnetically stirred at room temperature for 13 days, the remaining solid was separated for XRPD analysis. The results summarized in Table 5-e show that Forms A to D and Form J were obtained. [Table 5-e ] Summary of slurry experiments at room temperature Experiment ID Solvent ( v : v ) Solid form 3-07-A1 MTBE Type B 3-07-A2 _H2O Type A 3-07-A3 n-Heptane Low crystallinity 3-07-A4 Toluene Low crystallinity 3-07-A5 Hexane Type A 3-07-A6* IPA Type A 3-07-A7* 2-MeTHF Type B 3-07-A8* 1,4-Dioxane J-Type 3-07-A9 n-BuOH Low crystallinity 3-07-A10* MIBK Type A 3-07-A11 B O Type C 3-07-A12 IPA Type D 3-07-A13* acetone Amorphous 3-07-A14* DMF P-Type 3-07-A15 Anisole Type E 3-07-A16 THF/n-heptane (1:9) Low crystallinity 3-07-A17 2-MeTHF/n-heptane (1:9) Type A 3-07-A18 IPA/H2O (1:9) Type A 3-07-A19 IPAc/H2O (1:9) Type F 3-07-A20 n-BuOH/H2O (1:9) Type A 3-07-A21 n-BuOH/MTBE (1:9) Type A 3-07-A22 CHCl3/MTBE (1:9) Type A 3-07-A23* MeOH/H2O (937:63, aw=0.2) Amorphous 3-07-A24* MeOH/H2O (844:156, aw=0.4) N-type 3-07-A25* MeOH/H2O (693:304, aw=0.6) Type G 3-07-A26 MeOH/H2O (569:431, aw=0.8) Type G *: Solid obtained by slow evaporation at room temperature 5.2.2 Slow evaporation

在16種條件下進行緩慢蒸發實驗。簡而言之，將20 mg A型（3-05-A）溶解在20 mL玻璃小瓶中的0.2〜0.8 mL溶劑中。若未實現溶解，則使用PTFE（孔徑為0.2 μm）過濾懸浮液，並將濾液用於以下步驟。目視澄清的溶液被具有5〜10個針孔的Parafilm®覆蓋，並在室溫下蒸發。將分離出的固體用於XRPD分析。表5-f中總結的結果表明，獲得了A型、C型、D型、J型、K型、L型、N型、O型。 [表 5-f ]緩慢蒸發實驗的總結 實驗 ID 溶劑（ v : v ） 固體形式 3-08-A1 乙酸非晶形 3-08-A2 THF J型 3-08-A3 ACN 非晶形 3-08-A4 CHCl3 非晶形 3-08-A5 EtOAc C型 3-08-A6 DMSO 非晶形 3-08-A7 MeOH 非晶形 3-08-A8 EtOH N型 3-08-A9 1,4-二噁烷 J型 3-08-A10 n-BuOH A型 3-08-A11 MIBK O型 3-08-A12 BuOAc C型 3-08-A13 IPAc D型 3-08-A14 丙酮 K型 3-08-A15 DMF 凝膠 3-08-A16 2-MeTHF L型 5.2.3 緩慢冷卻 Slow evaporation experiments were performed under 16 conditions. Briefly, 20 mg of Form A (3-05-A) was dissolved in 0.2 to 0.8 mL of solvent in a 20 mL glass vial. If dissolution was not achieved, the suspension was filtered using PTFE (pore size 0.2 μm) and the filtrate was used in the following step. The visually clear solution was covered with Parafilm® with 5 to 10 pinholes and evaporated at room temperature. The separated solid was used for XRPD analysis. The results summarized in Table 5-f show that Form A, Form C, Form D, Form J, Form K, Form L, Form N, Form O were obtained. [ Table 5-f ] Summary of slow evaporation experiments Experiment ID Solvent ( v : v ) Solid form 3-08-A1 Acetic acid Amorphous 3-08-A2 THF J-Type 3-08-A3 ACN Amorphous 3-08-A4 CHCl3 Amorphous 3-08-A5 EtOAc Type C 3-08-A6 DMSO Amorphous 3-08-A7 MeOH Amorphous 3-08-A8 EtOH N-type 3-08-A9 1,4-Dioxane J-Type 3-08-A10 n-BuOH Type A 3-08-A11 MIBK Type O 3-08-A12 B O Type C 3-08-A13 IPA Type D 3-08-A14 acetone K-Type 3-08-A15 DMF Gel 3-08-A16 2-MeTHF L-type 5.2.3 Slow Cooling

在9種溶劑系統中進行緩慢冷卻實驗。在室溫下，將約20 mg A型（3-05-A）懸浮在3 mL玻璃小瓶中的1 mL溶劑中。然後將懸浮液加熱至50℃，平衡兩小時，並使用PTFE膜（孔徑為0.20 μm）過濾。將濾液以0.1℃/min的速率緩慢冷卻至5℃。表5-g中總結的結果表明，觀察到C型、G型、J型、L型及O型。 [表 5-g ]緩慢冷卻實驗的總結 實驗 ID 溶劑（ v : v ） 固體形式 3-09-A1* IPA O型 3-09-A2 2-MeTHF L型 3-09-A3* 1,4-二噁烷 J型 3-09-A4* n-BuOH L型 3-09-A5* 乙酸 G型（低結晶度） 3-09-A6 THF J型 3-09-A7* ACN 非晶形 3-09-A8 CHCl3 低結晶度 3-09-A9* EtOAc C型 *：室溫下從蒸發獲得的固體。5.2.4 反溶劑添加 Slow cooling experiments were performed in 9 solvent systems. About 20 mg of Form A (3-05-A) was suspended in 1 mL of solvent in a 3 mL glass vial at room temperature. The suspension was then heated to 50°C, equilibrated for two hours, and filtered using a PTFE membrane (pore size 0.20 μm). The filtrate was slowly cooled to 5°C at a rate of 0.1°C/min. The results summarized in Table 5-g show that Form C, Form G, Form J, Form L, and Form O were observed. [ Table 5-g ] Summary of slow cooling experiments Experiment ID Solvent ( v : v ) Solid form 3-09-A1* IPA Type O 3-09-A2 2-MeTHF L-type 3-09-A3* 1,4-Dioxane J-Type 3-09-A4* n-BuOH L-type 3-09-A5* Acetic acid Type G (low crystallinity) 3-09-A6 THF J-Type 3-09-A7* ACN Amorphous 3-09-A8 CHCl3 Low crystallinity 3-09-A9* EtOAc Type C *: Solid obtained from evaporation at room temperature. 5.2.4 Antisolvent addition

總共進行了9次反溶劑添加實驗。將約20 mg起始材料（3-05-A）溶解在0.2-1.4 mL溶劑中以獲得澄清溶液。磁力攪拌溶液，隨後逐步添加0.2 mL反溶劑直至出現沈澱或反溶劑的總量達到15.0 mL。分離獲得的沈澱用於XRPD分析。表5-h中的結果顯示，獲得了A型、C型、H型及I型。 [表 5-h ]反溶劑添加實驗的總結 實驗ID 溶劑反溶劑固體形式 3-10-A1* H2O 丙酮 H型 3-10-A2 THF 非晶形 3-10-A3* DMSO I型 3-10-A4* MTBE EtOH A型 3-10-A5* CHCl3 A型 3-10-A6 EtOAc A型 3-10-A7* 正庚烷丙酮 C型 3-10-A8* 2-MeTHF A型 3-10-A9* IPAc C型 *：室溫下從蒸發獲得的固體。5.2.5 液體蒸氣擴散 A total of 9 antisolvent addition experiments were performed. About 20 mg of the starting material (3-05-A) was dissolved in 0.2-1.4 mL of the solvent to obtain a clear solution. The solution was stirred magnetically, and then 0.2 mL of the antisolvent was gradually added until a precipitate appeared or the total amount of the antisolvent reached 15.0 mL. The precipitate obtained was separated for XRPD analysis. The results in Table 5-h show that Form A, Form C, Form H, and Form I were obtained. [ Table 5-h ] Summary of antisolvent addition experiments Experiment ID Solvent Antisolvent Solid form 3-10-A1* H2O acetone H-Type 3-10-A2 THF Amorphous 3-10-A3* DMSO Type I 3-10-A4* MTBE EtOH Type A 3-10-A5* CHCl3 Type A 3-10-A6 EtOAc Type A 3-10-A7* n-Heptane acetone Type C 3-10-A8* 2-MeTHF Type A 3-10-A9* IPA Type C *: Solids obtained from evaporation at room temperature. 5.2.5 Liquid vapor diffusion

進行了五次液體蒸氣擴散實驗。將約20 mg起始材料（3-05-A）溶解在適當的溶劑中，以在3 mL小瓶中獲得澄清溶液。然後將此溶液放入裝有3 mL揮發性溶劑的20 mL小瓶中。用蓋將20 mL小瓶密封並保持在室溫下，以留出足夠的時間使有機蒸氣與溶液相互作用。分離沈澱用於XRPD分析。表5-i中總結的結果顯示，產生了L型、M型及Q型。 [表 5-i ]液體蒸氣擴散實驗的總結 實驗 ID 溶劑 反溶劑 固體形式 3-11-A1 MIBK 正庚烷 Q型 3-11-A2 EtOAc IPA M型 3-11-A3 THF MTBE L型 3-11-A4 2-MeTHF 正庚烷 L型 3-11-A5* DMF 甲苯凝膠 *：室溫下藉由蒸發獲得固體。5.2.6 固體蒸氣擴散 Five liquid vapor diffusion experiments were performed. Approximately 20 mg of the starting material (3-05-A) was dissolved in an appropriate solvent to obtain a clear solution in a 3 mL vial. This solution was then placed in a 20 mL vial containing 3 mL of a volatile solvent. The 20 mL vial was sealed with a cap and kept at room temperature to allow sufficient time for the organic vapor to interact with the solution. The precipitate was separated for XRPD analysis. The results summarized in Table 5-i show that Form L, Form M, and Form Q were produced. [ Table 5-i ] Summary of liquid vapor diffusion experiments Experiment ID Solvent Antisolvent Solid form 3-11-A1 MIBK n-Heptane Q-Type 3-11-A2 EtOAc IPA Type M 3-11-A3 THF MTBE L-type 3-11-A4 2-MeTHF n-Heptane L-type 3-11-A5* DMF Toluene Gel *: Solids are obtained by evaporation at room temperature. 5.2.6 Solid vapor diffusion

使用6種不同的溶劑進行固體蒸氣擴散實驗。稱取約10 mg起始材料（3-05-A），放入3 mL小瓶中，然後將其放入裝有2 mL揮發性溶劑的20 mL小瓶中。將20 mL小瓶用蓋密封，並保持在室溫下7天，使溶劑蒸氣與樣本相互作用。藉由XRPD測試固體，表5-j中總結的結果顯示，產生了A型及M型。 [表 5-j ]固體蒸氣擴散實驗的總結 實驗 ID 溶劑 固體形式 3-12-A1 EtOH M型 3-12-A2 MTBE A型 3-12-A3 H2O A型 3-12-A4 丙酮非晶形 3-12-A5 2-MeTHF A型 3-12-A6 IPAc A型 5.2.7 溫度循環 Solid vapor diffusion experiments were performed using 6 different solvents. Approximately 10 mg of the starting material (3-05-A) was weighed into a 3 mL vial, which was then placed into a 20 mL vial containing 2 mL of a volatile solvent. The 20 mL vial was sealed with a cap and kept at room temperature for 7 days to allow the solvent vapor to interact with the sample. The solid was tested by XRPD, and the results summarized in Table 5-j show that Form A and Form M were produced. [ Table 5-j ] Summary of solid vapor diffusion experiments Experiment ID Solvent Solid form 3-12-A1 EtOH Type M 3-12-A2 MTBE Type A 3-12-A3 H2O Type A 3-12-A4 acetone Amorphous 3-12-A5 2-MeTHF Type A 3-12-A6 IPA Type A 5.2.7 Temperature cycle

在7種溶劑系統中進行溫度循環實驗。在室溫下，將約20 mg起始材料（3-05-A）懸浮在3 mL玻璃小瓶中的1 mL溶劑中。然後將懸浮液加熱至50℃，平衡一小時，並且使用PTFE膜（孔徑為0.20 μm）過濾。將濾液以0.2℃/min的速率緩慢冷卻至5℃，並且然後以1℃/min的速率加熱至50℃。再重複一次該循環，並且然後以0.2℃/min的速率冷卻至5℃。在分離固體並使用XRPD分析該等固體之前，將樣本在5℃下儲存。表5-k中總結的結果表明，觀察到A型、G型及O型。 [表 5-k ]溫度循環實驗的總結 實驗 ID 溶劑（ v : v ） 固體形式 3-13-A1* 2-MeTHF A型 3-13-A2* MeOH G型 3-13-A3* MIBK A型 3-13-A4* ACN 非晶形 3-13-A5 CHCl3 低結晶度 3-13-A6* 甲苯非晶形 3-13-A7* IPA O型 *：室溫下從蒸發獲得的固體。5.2.8 5 ℃ 下的漿液 Temperature cycling experiments were performed in 7 solvent systems. About 20 mg of the starting material (3-05-A) was suspended in 1 mL of solvent in a 3 mL glass vial at room temperature. The suspension was then heated to 50°C, equilibrated for one hour, and filtered using a PTFE membrane (pore size 0.20 μm). The filtrate was slowly cooled to 5°C at a rate of 0.2°C/min, and then heated to 50°C at a rate of 1°C/min. The cycle was repeated once more, and then cooled to 5°C at a rate of 0.2°C/min. The samples were stored at 5°C before the solids were separated and analyzed using XRPD. The results summarized in Table 5-k show that Form A, Form G, and Form O were observed. [ Table 5-k ] Summary of temperature cycle experiment Experiment ID Solvent ( v : v ) Solid form 3-13-A1* 2-MeTHF Type A 3-13-A2* MeOH Type G 3-13-A3* MIBK Type A 3-13-A4* ACN Amorphous 3-13-A5 CHCl3 Low crystallinity 3-13-A6* Toluene Amorphous 3-13-A7* IPA Type O *: Solids obtained from evaporation at room temperature. 5.2.8 Slurry at 5 °C

在不同的溶劑系統中於5℃下進行了漿液實驗。將約20 mg起始材料（3-05-A）懸浮在3-mL玻璃小瓶中的0.2 mL溶劑中。將懸浮液在5℃下磁力攪拌7天後，將剩餘的固體分離出來，用於XRPD分析。表5-l中總結的結果表明，獲得了A型、C型〜E型及J型。 [表 5-l ]5 ℃ 下的漿液實驗的總結 實驗 ID 溶劑（ v : v ） 固體形式 3-14-A1* BuOAc C型 3-14-A2* IPAc D型 3-14-A3* 丙酮低結晶度 3-14-A4* DMF 凝膠 3-14-A5 苯甲醚 E型 3-14-A6* 2MeTHF A型 3-14-A7* ACN 低結晶度 3-14-A8* CHCl3 低結晶度 3-14-A9* EtOAc 低結晶度 3-14-A10* MeOH C型 3-14-A11* THF J型 *：室溫下從蒸發獲得的固體。5.2.9 濕磨 Slurry experiments were performed at 5°C in different solvent systems. About 20 mg of the starting material (3-05-A) was suspended in 0.2 mL of solvent in a 3-mL glass vial. After the suspension was magnetically stirred at 5°C for 7 days, the remaining solid was separated and used for XRPD analysis. The results summarized in Table 5-1 show that Form A, Form C to Form E, and Form J were obtained. [ Table 5-1 ] Summary of slurry experiments at 5 °C Experiment ID Solvent ( v : v ) Solid form 3-14-A1* B O Type C 3-14-A2* IPA Type D 3-14-A3* acetone Low crystallinity 3-14-A4* DMF Gel 3-14-A5 Anisole Type E 3-14-A6* 2MeTHF Type A 3-14-A7* ACN Low crystallinity 3-14-A8* CHCl3 Low crystallinity 3-14-A9* EtOAc Low crystallinity 3-14-A10* MeOH Type C 3-14-A11* THF J-Type *: Solids obtained from evaporation at room temperature. 5.2.9 Wet grinding

在五種條件下進行濕磨實驗。簡而言之，將10 mg A型（3-05-A）放入研缽中，並在約20 µL溶劑中研磨5 min。將分離出的固體用於XRPD分析。表5-m中總結的結果表明獲得了A型。 [表 5-m ]濕磨實驗的總結 實驗 ID 溶劑（ v ： v ） 固體形式 3-15-A1 MTBE 非晶形 3-15-A2 H₂ O 非晶形 3-15-A3 正庚烷非晶形 3-15-A4 甲苯非晶形 3-15-A5 己烷非晶形 3-15-A6 IPA 非晶形 3-15-A7 2-MeTHF A型（低結晶度） 3-15-A8 1,4-二噁烷 A型 3-15-A9 n-BuOH 非晶形 3-15-A10 MIBK 非晶形 [表 5-1 ]間二酮 DBTA 共晶體形式的表徵 晶體形式 （批號） 製備條件 TGA 中的重量損失（ % ） DSC 吸熱（峰， ℃ ）形式 ID A型（3-05-A）用DBTA（2-MeTHF）的經典拆分高達125℃時為7.31 109.4 120.0 2-MeTHF溶劑化物 B型（3-07-A1）室溫下的漿液（MTBE）高達125℃時為7.21 115.7 MTBE溶劑化物 C型（3-08-A5）緩慢蒸發（EtOAc）高達125℃時為7.99 92.7 116.4 EtOAc溶劑化物 D型（3-07-A12）室溫下的漿液（IPAc）高達130℃時為7.51。 75.4, 110.5, 148.0, 116.6 , 265.9（放熱）。 IPAc溶劑化物 E型（3-07-A15）室溫下的漿液（苯甲醚）高達125℃時為8.63 103.8 119.0 苯甲醚溶劑化物 F型（3-07-A19）室溫下的漿液IPAc/H₂ O （v:v 1:9）高達130℃時為6.2 86.5, 107.9 IPAc溶劑化物 G型（3-07-A26）室溫下的漿液（MeOH/H₂ O aw=0.8）高達100℃時為6.44 86.0 127.2 133.1 水合物 H型（3-10-A1）反溶劑（丙酮/H₂ O）高達130℃時為3.58 107.6 丙酮溶劑化物 I型（3-10-A3）反溶劑（DMSO/H₂ O）高達150℃時為7.26 128.9 DMSO溶劑化物 J型（3-08-A2）緩慢蒸發（THF） 125℃時為7.27% 115.7 THF溶劑化物 K型（3-08-A14）緩慢蒸發（丙酮）高達150℃時為5.71 96.7, 119.8 147.4 157.4℃（放熱）。丙酮溶劑化物 L型（3-11-A4）液體蒸氣擴散（2-MeTHF/正庚烷）高達130℃時為7.94 126.2 2-MeTHF溶劑化物 M型（3-11-A2）液體蒸氣擴散（EtOAc/IPA）高達150℃時為3.73 122.6 IPA溶劑化物 N型（3-08-A8）緩慢蒸發（EtOH）高達150℃時為4.08 85.4, 126.5 150.9 EtOH溶劑化物 O型（3-08-A11）緩慢蒸發（MIBK）高達130℃時為2.03 106.2, 151.2 MIBK溶劑化物 P型（3-07-A14）緩慢蒸發（DMF）高達130℃時為8.33 89.9 DMF溶劑化物 Q型（3-11-A1）液體蒸氣擴散（MIBK/正庚烷）高達120℃時為6.00 92.9, 148.9^, 170.0 MIBK溶劑化物 5.3 A 型 Wet milling experiments were performed under five conditions. Briefly, 10 mg of Form A (3-05-A) was placed in a mortar and ground in approximately 20 µL of solvent for 5 min. The separated solid was used for XRPD analysis. The results summarized in Table 5-m show that Form A was obtained. [ Table 5-m ] Summary of wet milling experiments Experiment ID Solvent ( v : v ) Solid form 3-15-A1 MTBE Amorphous 3-15-A2 _H2O Amorphous 3-15-A3 n-Heptane Amorphous 3-15-A4 Toluene Amorphous 3-15-A5 Hexane Amorphous 3-15-A6 IPA Amorphous 3-15-A7 2-MeTHF Type A (low crystallinity) 3-15-A8 1,4-Dioxane Type A 3-15-A9 n-BuOH Amorphous 3-15-A10 MIBK Amorphous [ Table 5-1 ] Characterization of the diketone DBTA co-crystal form Crystalline form (lot number) Preparation conditions Weight loss in TGA ( % ) DSC endothermic (peak, ℃ ) Form ID Type A (3-05-A) Classical separation using DBTA (2-MeTHF) 7.31 at 125℃ 109.4 120.0 2-MeTHF solvent Type B (3-07-A1) Slurry at room temperature (MTBE) 7.21 at 125℃ 115.7 MTBE solvent Type C (3-08-A5) Slow evaporation (EtOAc) 7.99 at up to 125℃ 92.7 116.4 EtOAc solvent Type D (3-07-A12) Slurry at room temperature (IPAc) At up to 130℃, it is 7.51. 75.4, 110.5, 148.0, 116.6, 265.9 (exothermic). IPAc solvent Type E (3-07-A15) Slurry at room temperature (anisole) 8.63 at 125℃ 103.8 119.0 Anisole Solvent Type F (3-07-A19) Slurry IPAc/H ₂ O (v:v 1:9) at room temperature 6.2 at up to 130℃ 86.5, 107.9 IPAc solvent Type G (3-07-A26) Slurry at room temperature (MeOH/H ₂ O aw=0.8) 6.44 at 100℃ 86.0 127.2 133.1 Hydrate H type (3-10-A1) Antisolvent (acetone/H ₂ O) 3.58 at 130℃ 107.6 Acetone Solvent Type I (3-10-A3) Antisolvent (DMSO/H ₂ O) 7.26 at 150℃ 128.9 DMSO solvent Type J (3-08-A2) Slow evaporation (THF) 7.27% at 125℃ 115.7 THF solvent Type K (3-08-A14) Slow evaporation (acetone) 5.71 at 150℃ 96.7, 119.8 147.4 157.4℃ (exothermic). Acetone Solvent L type (3-11-A4) Liquid vapor diffusion (2-MeTHF/n-heptane) 7.94 at 130℃ 126.2 2-MeTHF solvent Type M (3-11-A2) Liquid vapor diffusion (EtOAc/IPA) 3.73 at 150℃ 122.6 IPA Solvent Type N (3-08-A8) Slow evaporation (EtOH) 4.08 at up to 150℃ 85.4, 126.5 150.9 EtOH solvent Type O (3-08-A11) Slow evaporation (MIBK) 2.03 at 130℃ 106.2, 151.2 MIBK solvent Type P (3-07-A14) Slow evaporation (DMF) 8.33 at 130℃ 89.9 DMF solvent Q type (3-11-A1) Liquid vapor diffusion (MIBK/n-heptane) 6.00 at up to 120℃ 92.9, 148.9 ^, 170.0 MIBK solvent 5.3 Type A

A型（3-05-A）由客戶提供。圖5-4中顯示的XRPD結果表明為結晶。如圖5-5中的TGA及DSC資料所示，高達125℃時，重量損失了7.3%，在109.4及120.0℃（峰值）下觀察到兩個吸熱峰。如圖5-6所示，在¹ H NMR譜圖中證實2-MeTHF的存在。基於結果，A型被認為係2-MeTHF溶劑化物。5.4 B 型 Form A (3-05-A) was provided by the customer. The XRPD results shown in Figure 5-4 indicate that it is crystalline. As shown in the TGA and DSC data in Figure 5-5, a weight loss of 7.3% was observed at up to 125°C, and two endothermic peaks were observed at 109.4 and 120.0°C (peaks). As shown in Figure 5-6, the presence of 2-MeTHF was confirmed in the ¹ H NMR spectrum. Based on the results, Form A was considered to be a 2-MeTHF solvate. 5.4 Form B

在室溫下藉由A型在MTBE中的漿液獲得B型樣本（3-07-A1）。圖5-7中顯示的XRPD圖表明為結晶。如圖5-10中的TGA及DSC資料所示，高達125℃時，重量損失了7.2%，並且在115.7℃（峰值）下觀察到吸熱峰。如圖5-9所示，在¹ H NMR譜圖中證實MTBE的存在。基於結果，B型可能是MTBE溶劑化物。5.5 C 型 A sample of Form B (3-07-A1) was obtained from a slurry of Form A in MTBE at room temperature. The XRPD pattern shown in Figure 5-7 indicates crystallization. As shown in the TGA and DSC data in Figure 5-10, a weight loss of 7.2% was observed up to 125°C, and an endothermic peak was observed at 115.7°C (peak). The presence of MTBE was confirmed in the ¹ H NMR spectrum, as shown in Figure 5-9. Based on the results, Form B is likely a MTBE solvate. 5.5 Form C

藉由在室溫下在EtOAc中緩慢蒸發來獲得C型樣本（3-08-A5）。圖5-10中顯示的XRPD圖表明為結晶。圖5-11中顯示的TGA及DSC資料表明，高達125℃時，重量損失了8.0%，並且在92.7℃及116.4℃（峰值）下有兩個吸熱峰。如圖5-12所示，在¹ H NMR譜圖中證實EtOAc的存在。基於結果，C型可能是EtOAc溶劑化物。5.6 D 型 A sample of Form C (3-08-A5) was obtained by slow evaporation in EtOAc at room temperature. The XRPD pattern shown in Figure 5-10 indicates crystallinity. The TGA and DSC data shown in Figure 5-11 indicate a weight loss of 8.0% up to 125°C and two endothermic peaks at 92.7°C and 116.4°C (peaks). The presence of EtOAc was confirmed in the ¹ H NMR spectrum as shown in Figure 5-12. Based on the results, Form C is likely an EtOAc solvate. 5.6 Form D

藉由在室溫下A型在IPAc中的漿液獲得D型（3-07-A12）。圖5-13中顯示的XRPD結果表明為結晶。如圖5-14中的TGA及DSC資料所示，高達130℃時，重量損失了7.5%，並且在75.4℃、110.5℃、148.0℃及116.6℃（峰值）下有吸熱峰，並且在265.9℃下觀察到放熱峰。如圖5-15所示，在¹ H NMR譜圖中證實IPAc的存在。基於結果，D型可能是IPAc溶劑化物。5.7 E 型 Form D (3-07-A12) was obtained by slurrying Form A in IPAc at room temperature. The XRPD results shown in Figure 5-13 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-14, there was a weight loss of 7.5% up to 130°C, and there were endothermic peaks at 75.4°C, 110.5°C, 148.0°C, and 116.6°C (peak), and an exothermic peak was observed at 265.9°C. The presence of IPAc was confirmed in the ¹ H NMR spectrum as shown in Figure 5-15. Based on the results, Form D is likely an IPAc solvate. 5.7 Form E

藉由在室溫下A型在苯甲醚中的漿液獲得E型（3-07-A15）。圖5-16中顯示的XRPD結果表明為結晶。如圖5-17中的TGA及DSC資料所示，高達125℃時，重量損失了8.6%，並且在103.8℃及119.0℃（峰值）下觀察到兩個吸熱峰。如圖5-18所示，在¹ H NMR譜圖中證實IPAc的存在。基於結果，E型可能是苯甲醚溶劑化物。5.8 F 型 Form E (3-07-A15) was obtained by slurrying Form A in anisole at room temperature. The XRPD results shown in Figure 5-16 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-17, up to 125°C, there was a weight loss of 8.6%, and two endothermic peaks were observed at 103.8°C and 119.0°C (peaks). The presence of IPAc was confirmed in the ¹ H NMR spectrum as shown in Figure 5-18. Based on the results, Form E is likely an anisole solvate. 5.8 Form F

在室溫下藉由A型在IPAc/H₂ O（v：v 1:9）中的漿液獲得F型（3-07-A19）。圖5-19中顯示的XRPD結果表明為結晶。如圖5-20中的TGA及DSC資料所示，高達130℃時，重量損失了6.2%，並且在86.5℃及107.9℃（峰值）下觀察到兩個吸熱峰。如圖5-18所示，在¹ H NMR譜圖中證實IPAc的存在。基於結果，F型可能是IPAc溶劑化物。5.9 G 型 Form F (3-07-A19) was obtained from a slurry of Form A in IPAc/H ₂ O (v:v 1:9) at room temperature. The XRPD results shown in Figure 5-19 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-20, a weight loss of 6.2% was observed up to 130°C, and two endothermic peaks were observed at 86.5°C and 107.9°C (peaks). The presence of IPAc was confirmed in the ¹ H NMR spectrum as shown in Figure 5-18. Based on the results, Form F is likely an IPAc solvate. 5.9 Form G

在室溫下藉由A型在MeOH/H₂ O （aw=0.8）中的漿液獲得G型（3-07-A26）。圖5-22中顯示的XRPD結果表明為結晶狀態。如圖5-23中的TGA及DSC資料所示，高達100℃時，重量損失了6.4%，並且在86.0℃、127.2℃及133.1℃（峰值）下觀察到吸熱峰。如圖5-24所示，在溶液¹ HNMR譜圖中未觀察到MeOH或MeTHF信號。基於結果，G型可能是水合物。5.10 H 型 Form G (3-07-A26) was obtained from a slurry of Form A in MeOH/H ₂ O (aw=0.8) at room temperature. The XRPD results shown in Figure 5-22 indicate a crystalline state. As shown in the TGA and DSC data in Figure 5-23, a weight loss of 6.4% was observed up to 100°C, and endothermic peaks were observed at 86.0°C, 127.2°C, and 133.1°C (peak). As shown in Figure 5-24, no MeOH or MeTHF signals were observed in the solution ¹ H NMR spectrum. Based on the results, Form G is likely a hydrate. 5.10 Form H

使用丙酮/H₂ O藉由反溶劑添加獲得H型（3-10-A1）。圖5-25中顯示的XRPD結果表明為結晶。如圖5-26中的TGA及DSC資料所示，高達130℃時，重量損失了3.6%，並且在107.6℃（峰值）下觀察到吸熱峰。如圖5-27所示，在¹ H NMR譜圖中證實丙酮的存在。基於結果，H型可能是丙酮溶劑化物。5.11 I 型 Form H (3-10-A1) was obtained by anti-solvent addition using acetone/H ₂ O. The XRPD results shown in Figure 5-25 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-26, a weight loss of 3.6% was observed up to 130°C, and an endothermic peak was observed at 107.6°C (peak). The presence of acetone was confirmed in the ¹ H NMR spectrum as shown in Figure 5-27. Based on the results, Form H is likely an acetone solvate. 5.11 Form I

使用DMSO/H₂ O藉由反溶劑添加獲得I型（3-10-A3）。圖5-28中顯示的XRPD結果表明為結晶。如圖5-29中的TGA及DSC資料所示，高達150℃時，重量損失了7.3%，並且在128.9℃（峰值）下觀察到吸熱峰。如圖5-30所示，在¹ H NMR譜圖中證實DMSO的存在。基於結果，I型可能是DMSO溶劑化物。5.12 J 型 Form I (3-10-A3) was obtained by anti-solvent addition using DMSO/H ₂ O. The XRPD results shown in Figure 5-28 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-29, a weight loss of 7.3% was observed up to 150°C, and an endothermic peak was observed at 128.9°C (peak). The presence of DMSO was confirmed in the ¹ H NMR spectrum as shown in Figure 5-30. Based on the results, Form I is likely a DMSO solvate. 5.12 Form J

藉由在THF中緩慢蒸發獲得J型（3-08-A2）。圖5-31中顯示的XRPD結果表明為結晶。如圖5-32中的TGA及DSC資料所示，高達125℃時，重量損失了7.3%，並且在115.7℃（峰值）下觀察到吸熱峰。如圖5-33所示，在¹ H NMR譜圖中證實THF的存在。基於結果，J型可能是THF溶劑化物。5.13 K 型 Form J (3-08-A2) was obtained by slow evaporation in THF. The XRPD results shown in Figure 5-31 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-32, a weight loss of 7.3% was observed up to 125°C, and an endothermic peak was observed at 115.7°C (peak). The presence of THF was confirmed in the ¹ H NMR spectrum as shown in Figure 5-33. Based on the results, Form J is likely a THF solvate. 5.13 Form K

藉由在丙酮中緩慢蒸發獲得K型（3-08-A14）。圖5-34中顯示的XRPD結果表明為結晶。如圖5-35中的TGA及DSC資料所示，高達150℃時，重量損失了5.7%，並且在96.7℃、119.8℃及147.4℃（峰值）下觀察到吸熱峰，並且在157.4℃（峰值）下觀察到放熱峰。如圖5-36所示，在¹ H NMR譜圖中證實丙酮的存在。基於結果，K型可能是丙酮溶劑化物。5.14 L 型 Form K (3-08-A14) was obtained by slow evaporation in acetone. The XRPD results shown in Figure 5-34 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-35, up to 150°C, there was a weight loss of 5.7%, and endothermic peaks were observed at 96.7°C, 119.8°C, and 147.4°C (peak), and an exothermic peak was observed at 157.4°C (peak). The presence of acetone was confirmed in the ¹ H NMR spectrum, as shown in Figure 5-36. Based on the results, Form K is likely an acetone solvate. 5.14 Form L

藉由在2-MeTHF/正庚烷中的液體蒸氣擴散獲得L型（3-11-A4）。圖5-37中顯示的XRPD結果表明具有較佳的取向的結晶。如圖5-38中的TGA及DSC資料所示，高達130℃時，重量損失了7.9%，並且在126.2℃（峰值）下觀察到吸熱峰。如圖5-39所示，在¹ H NMR譜圖中證實丙酮的存在，而沒有觀察到正庚烷信號。基於結果，L型可能是2-MeTHF溶劑化物。5.15 M 型 Form L (3-11-A4) was obtained by liquid vapor diffusion in 2-MeTHF/n-heptane. The XRPD results shown in Figure 5-37 indicate crystals with better orientation. As shown in the TGA and DSC data in Figure 5-38, a weight loss of 7.9% was observed up to 130°C, and an endothermic peak was observed at 126.2°C (peak). As shown in Figure 5-39, the presence of acetone was confirmed in the ¹ H NMR spectrum, while no n-heptane signal was observed. Based on the results, Form L is likely a 2-MeTHF solvate. 5.15 Form M

從在EtOAc/IPA中的液體蒸氣擴散獲得M型（3-11-A2）。圖5-40中顯示的XRPD結果表明為結晶。如圖5-41中的TGA及DSC資料所示，高達150℃時，重量損失了3.7%，並且在122.6℃（峰值）下觀察到吸熱峰。如圖5-42所示，在¹ H NMR中證實IPA的存在，而沒有觀察到EtOAc信號。基於結果，M型可能是IPA溶劑化物。5.16 N 型 Form M (3-11-A2) was obtained from liquid vapor diffusion in EtOAc/IPA. The XRPD results shown in Figure 5-40 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-41, a weight loss of 3.7% was observed up to 150°C, and an endothermic peak was observed at 122.6°C (peak). As shown in Figure 5-42, the presence of IPA was confirmed in the ¹ H NMR, while no EtOAc signal was observed. Based on the results, Form M is likely an IPA solvate. 5.16 Form N

藉由在EtOH中緩慢蒸發獲得N型（3-08-A8）。圖5-43中顯示的XRPD結果表明為結晶。如圖5-44中的TGA及DSC資料所示，高達150℃時，重量損失了4.1%，並且在85.4℃、126.5℃及150.9℃（峰值）下觀察到吸熱峰。如圖5-45所示，在¹ H NMR譜圖中證實EtOH的存在。基於結果，N型可能是EtOH溶劑化物。5.17 O 型 Form N (3-08-A8) was obtained by slow evaporation in EtOH. The XRPD results shown in Figure 5-43 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-44, a weight loss of 4.1% was observed up to 150°C, and endothermic peaks were observed at 85.4°C, 126.5°C, and 150.9°C (peak). The presence of EtOH was confirmed in the ¹ H NMR spectrum as shown in Figure 5-45. Based on the results, Form N is likely an EtOH solvate. 5.17 Form O

藉由在MIBK中的緩慢蒸發獲得O型（3-08-A11）。圖5-46中顯示的XRPD結果表明為結晶。如圖5-47中的TGA及DSC資料所示，高達130℃時，重量損失了2.0%，並且在106.2℃及151.2℃（峰值）下觀察到兩個吸熱峰。如圖5-48所示，在¹ H NMR譜圖中證實MIBK的存在。基於結果，O型可能是MIBK溶劑化物。5.18 P 型 Form O (3-08-A11) was obtained by slow evaporation in MIBK. The XRPD results shown in Figure 5-46 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-47, a weight loss of 2.0% was observed up to 130°C, and two endothermic peaks were observed at 106.2°C and 151.2°C (peaks). The presence of MIBK was confirmed in the ¹ H NMR spectrum as shown in Figure 5-48. Based on the results, Form O is likely a MIBK solvate. 5.18 Form P

藉由在DMF中的緩慢蒸發獲得P型（3-07-A14）。圖5-49中顯示的XRPD結果表明為結晶。如圖5-50中的TGA及DSC資料所示，高達130℃時，重量損失了8.3%，並且在89.9℃（峰值）下觀察到吸熱峰。如圖5-51所示，在¹ H NMR譜圖中證實DMF的存在。基於結果，P型可能是DMF溶劑化物。5.19 Q 型 Form P (3-07-A14) was obtained by slow evaporation in DMF. The XRPD results shown in Figure 5-49 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-50, a weight loss of 8.3% was observed up to 130°C, and an endothermic peak was observed at 89.9°C (peak). The presence of DMF was confirmed in the ¹ H NMR spectrum as shown in Figure 5-51. Based on the results, Form P is likely a DMF solvate. 5.19 Form Q

藉由在MIBK/正庚烷中的液體蒸氣擴散獲得Q型（3-11-A1）。圖5-52中顯示的XRPD結果表明為結晶。如圖5-53中的TGA及DSC資料所示，高達120℃時，重量損失了6.0%，並且在92.9℃、148.9℃及170.0℃（峰值）下觀察到吸熱峰。如圖5-54所示，在¹ H NMR譜圖中證實MIBK的存在，並未觀察到正庚烷信號。基於結果，Q型可能是MIBK溶劑化物。6. 組成物 4a 的晶體資料及實驗 Form Q (3-11-A1) was obtained by liquid vapor diffusion in MIBK/n-heptane. The XRPD results shown in Figure 5-52 indicate crystallinity. As shown in the TGA and DSC data in Figure 5-53, a weight loss of 6.0% was observed up to 120°C, and endothermic peaks were observed at 92.9°C, 148.9°C, and 170.0°C (peak). As shown in Figure 5-54, the presence of MIBK was confirmed in the ¹ H NMR spectrum, and no n-heptane signal was observed. Based on the results, Form Q is likely a MIBK solvate. 6. Crystalline data and experiments of composition 4a

實驗。 按原樣使用（組成物 4a ）的單一無色片狀晶體。選擇適合的晶體（0.28 × 0.18 × 0.09） mm³ ，並將其與巴拉東油（paratone oil）一起安裝在Bruker APEX-II CCD衍射儀上的尼龍環上。在資料收集期間，使晶體保持在T = 173(2) K。使用Olex2 （Dolomanov等人, 2009），藉由XT（Sheldrick, 2015）結構求解程式，使用固有相求解方法對結構進行求解。使用最小二乘最小化對模型進行XL 版本（Sheldrick，2008）改善。 Experimental. A single colorless plate-like crystal of ( composition 4a ) was used as received. A suitable crystal (0.28 × 0.18 × 0.09) mm ³ was selected and mounted on a nylon ring with paratone oil on a Bruker APEX-II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. The structure was solved using the intrinsic phase solver with the XT (Sheldrick, 2015) structure solver using Olex2 (Dolomanov et al., 2009). The model was refined using the XL version (Sheldrick, 2008) using least squares minimization.

晶體資料。 C₆₅ H₇₂ Cl₂ F₂ N₈ O₁₅ ,M_r = 1314.20, 三斜晶系,P 1 （No. 1）, a = 11.5683（10） Å, b = 11.6705（10） Å, c = 13.9593（12） Å,α = 68.1780（10）^° ,β = 69.4150（10）^° ,γ = 87.7760（10）^° ,V = 1628.7（2） Å³ ,T = 173（2） K,Z = 1,Z’ = 1,μ （MoK _α ） = 0.178, 量測到26758次反射, 11949次唯一反射（R_int = 0.0528）用於所有計算。最終的wR₂ 為0.2465（所有資料），並且R₁ 為0.0835 （I ＞ 2（I））。p [表 6-2 ]：組成物 4A 的分數原子座標（×10⁴ ）及等效各向同性位移參數（Å² × 10³ ）。U_eq 定義為正交U_ij 的跡線的1/3。原子 x y z U_eq O1C 5607（5） 3451（5） 6493（5） 44.9（14） O2C 6723（6） 4580（6） 6921（5） 49.9（15） O3C 3704（5） 3216（6） 5826（5） 45.6（14） O4C 2800（6） 3841（6） 4560（6） 55.9（16） O5C 3369（5） 5630（6） 6567（5） 50.2（15） O6C 3636（5） 3990（6） 7917（5） 50.8（15） O7C 5703（6） 2984（7） 4257（5） 55.4（16） O8C 6595（5） 4867（6） 3832（5） 49.1（15） C1C 5032（7） 4527（8） 6031（7） 41（2） C2C 4615（7） 4267（8） 5203（7） 39.1（19） C3C 3928（8） 4667（8） 6968（7） 42（2） C4C 5705（8） 3954（9） 4361（7） 42（2） C5C 6393（8） 3601（8） 6961（7） 42（2） C6C 6820（9） 2403（8） 7493（8） 49（2） C7C 7721（15） 2378（12） 7941（13） 98（3） C8C 8179（15） 1311（13） 8410（13） 94（3） C9C 7697（17） 223（14） 8497（14） 107（5） C10C 6708（16） 185（12） 8178（13） 98（3） C11C 6265（15） 1303（12） 7665（13） 94（3） C12C 2953（8） 3028（9） 5341（7） 44（2） C13C 2359（9） 1762（9） 5860（8） 54（2） C14C 1223（9） 1501（10） 5822（8） 56（2） C15C 671（11） 300（12） 6312（10） 75（3） C16C 1261（14） -658（13） 6805（13） 98（5） C17C 2446（14） -407（13） 6720（13） 97（4） C18C 2954（13） 800（12） 6325（12） 87（4） Cl1B 6935（2） 1601（2） 11106（2） 66.0（7） F1B 4643（5） 1859（6） 10647（5） 66.7（16） O1B 8509（6） 7968（6） 7303（6） 58.0（17） O2B 4575（6） 6378（7） 8234（6） 66.1（19） N1B 7896（6） 6005（6） 8607（6） 40.4（16） N2B 7345（6） 3931（7） 9798（6） 42.2（17） N3B 6567（7） 7139（7） 7745（6） 49.2（18） N4B 11242（6） 5811（7） 8040（6） 47.4（18） C1B 7710（8） 7096（9） 7832（8） 48（2） C2B 7030（8） 4974（8） 9152（6） 40（2） C3B 6537（8） 2952（9） 10275（7） 47（2） C4B 5411（8） 2909（8） 10151（7） 47（2） C5B 5070（8） 3977（10） 9543（7） 49（2） C6B 5884（8） 5054（9） 9031（7） 44（2） C7B 5584（8） 6210（9） 8328（8） 50（2） C8B 9103（7） 5996（7） 8717（7） 41（2） C9B 9205（8） 6331（8） 9550（7） 43（2） C10B 10370（9） 6393（9） 9588（7） 49（2） C11B 11350（8） 6131（8） 8840（7） 44（2） C12B 10113（7） 5734（7） 7981（7） 38.9（19） C13B 8078（9） 6634（9） 10360（8） 55（2） C14B 10040（9） 5292（9） 7127（8） 54（2） C15B 10546（10） 4041（10） 7234（10） 65（3） C16B 10688（11） 6301（12） 5939（9） 73（3） Cl1A 11316（3） -588（3） 4003（3） 82.7（9） F1A 13799（6） -251（6） 4033（5） 77.9（18） O1A 12158（6） 6025（6） 1115（6） 57.3（17） O2A 15430（6） 4363（7） 1981（6） 63.4（18） N1A 11949（6） 3944（6） 2039（6） 38.9（16） N2A 11735（7） 1804（7） 3004（6） 48.6（19） N3A 13776（6） 5170（7） 1580（6） 45.5（18） N4A 8608（6） 4153（7） 2689（6） 46.4（18） C1A 12607（8） 5110（9） 1551（7） 47（2） C2A 12449（7） 2876（8） 2555（7） 40（2） C3A 12216（10） 797（10） 3464（8） 56（2） C4A 13389（10） 813（9） 3546（8） 56（3） C5A 14083（9） 1886（10） 3114（8） 54（2） C6A 13638（8） 2995（8） 2564（7） 44（2） C7A 14365（8） 4199（9） 2043（8） 48（2） C8A 10709（7） 3834（8） 2039（6） 37.4（19） C9A 10540（8） 3371（9） 1305（8） 47（2） C10A 9326（8） 3313（8） 1314（7） 47（2） C11A 8421（8） 3689（8） 2008（7） 45（2） C12A 9733（7） 4227（7） 2738（7） 39.4（19） C13A 11568（8） 2995（10） 522（8） 55（2） C14A 9890（8） 4703（9） 3549（7） 50（2） C15A 9619（11） 6056（11） 3255（11） 71（3） C16A 9045（10） 3875（11） 4734（8） 64（3） O3S 355（10） 1070（10） 9718（9） 116（3） C11S -300（40） -220（40） 11630（40） 142（14） C11T -1050（40） -700（50） 11410（40） 190（20） C12S 160（30） -310（30） 10410（20） 180（9） C13S 1360（40） -510（50） 10600（40） 151（11） C13T 1220（40） -820（40） 9990（40） 151（11） C14S 2240（20） 280（20） 9240（20） 155（8） C15S 1510（20） 1150（20） 8834（18） 139（7） O2S 6461（8） -721（8） 5995（7） 83（2） C6S 5780（20） -1920（20） 5275（19） 145（7） C7S 6000（20） -720（20） 5170（20） 155（8） C8S 7200（30） -180（30） 4150（30） 241（15） C9S 7990（20） 670（20） 4390（20） 153（7） C10S 7490（30） 340（30） 5490（30） 202（11） O1S 4966（9） 7468（9） 1097（8） 99（3） C1S 5930（20） 8160（20） 2110（20） 176（9） C2S 5018（15） 7306（16） 2147（14） 105（5） C3S 3770（20） 7280（20） 2920（20） 146（7） C4S 3200（30） 8270（30） 2170（30） 207（12） C5S 4180（20） 8430（20） 990（20） 162（8） [表 6-3 ]：各向異性位移參數（×10⁴ ）組成物 4A 。各向異性位移因子指數採用以下形式：-2π² [h² a*² ×U₁₁ + ... +2hka* × b* ×U₁₂ ]$ 原子 U₁₁ U₂₂ U₃₃ U₂₃ U₁₃ U₁₂ O1C 37（3） 57（4） 52（3） -27（3） -25（3） 9（3） O2C 47（4） 54（4） 52（4） -21（3） -21（3） 4（3） O3C 33（3） 63（4） 39（3） -21（3） -10（3） -3（3） O4C 52（4） 68（4） 53（4） -20（4） -26（3） 1（3） O5C 34（3） 56（4） 53（4） -19（3） -11（3） 9（3） O6C 44（3） 71（4） 35（4） -21（3） -11（3） 3（3） O7C 46（4） 71（5） 56（4） -34（4） -15（3） 3（3） O8C 33（3） 56（4） 55（4） -22（3） -11（3） 7（3） C1C 31（4） 48（5） 47（5） -20（4） -14（4） 1（4） C2C 35（5） 42（5） 41（5） -16（4） -14（4） 2（4） C3C 37（5） 52（5） 39（5） -21（4） -14（4） 2（4） C4C 36（5） 51（5） 45（5） -17（4） -22（4） 6（4） C5C 40（5） 48（5） 35（4） -16（4） -11（4） 5（4） C6C 58（6） 45（5） 51（5） -22（4） -26（5） 10（4） C7C 141（9） 68（6） 117（8） -37（6） -85（8） 23（6） C8C 124（9） 77（6） 120（8） -41（6） -86（7） 41（6） C9C 155（14） 87（10） 133（13） -53（9） -107（12） 68（10） C10C 141（9） 68（6） 117（8） -37（6） -85（8） 23（6） C11C 124（9） 77（6） 120（8） -41（6） -86（7） 41（6） C12C 35（5） 65（6） 38（5） -26（5） -15（4） 3（4） C13C 50（6） 59（6） 56（6） -23（5） -23（5） 6（5） C14C 47（6） 71（7） 58（6） -31（5） -22（5） 1（5） C15C 54（6） 101（10） 73（8） -34（7） -22（6） -21（6） C16C 96（10） 81（9） 114（11） -3（8） -67（9） -27（8） C17C 98（10） 73（8） 110（11） -10（8） -51（9） -2（7） C18C 88（9） 77（8） 102（10） -20（7） -56（8） -9（7） Cl1B 67.9（16） 57.4（14） 64.2（16） -10.1（12） -27.3（13） -6.4（12） F1B 67（4） 76（4） 55（3） -19（3） -22（3） -23（3） O1B 41（4） 55（4） 71（4） -12（3） -23（3） -6（3） O2B 36（4） 89（5） 78（5） -31（4） -28（3） 11（3） N1B 23（3） 42（4） 51（4） -12（3） -13（3） -6（3） N2B 33（4） 54（5） 35（4） -14（3） -10（3） -5（3） N3B 40（4） 58（5） 48（4） -12（4） -23（4） 2（4） N4B 35（4） 47（4） 59（5） -17（4） -18（4） 7（3） C1B 38（5） 55（6） 58（6） -27（5） -22（4） 9（5） C2B 37（5） 53（5） 27（4） -15（4） -9（4） 1（4） C3B 46（5） 55（6） 40（5） -19（4） -14（4） 6（4） C4B 49（5） 54（6） 36（5） -16（4） -14（4） -12（4） C5B 29（5） 83（7） 35（5） -25（5） -9（4） -6（5） C6B 32（5） 64（6） 37（5） -21（4） -10（4） -8（4） C7B 38（5） 67（6） 50（5） -23（5） -19（4） 3（4） C8B 34（5） 43（5） 48（5） -15（4） -19（4） 2（4） C9B 39（5） 51（5） 42（5） -22（4） -12（4） 1（4） C10B 49（6） 59（6） 42（5） -20（4） -20（4） 10（4） C11B 42（5） 50（5） 46（5） -17（4） -23（4） 4（4） C12B 28（4） 42（5） 47（5） -17（4） -14（4） 2（3） C13B 44（5） 62（6） 52（6） -25（5） -8（4） 7（5） C14B 40（5） 62（6） 61（6） -26（5） -18（5） 0（4） C15B 52（6） 72（7） 89（8） -52（6） -22（6） 7（5） C16B 66（7） 99（9） 50（6） -23（6） -21（5） -10（6） Cl1A 84（2） 60.8（16） 85（2） -4.6（15） -34.1（16） -3.2（14） F1A 89（5） 73（4） 76（4） -21（3） -45（4） 31（3） O1A 45（4） 60（4） 64（4） -17（4） -23（3） 1（3） O2A 42（4） 87（5） 76（5） -38（4） -33（3） 8（3） N1A 26（3） 53（4） 37（4） -16（3） -12（3） 1（3） N2A 41（4） 59（5） 37（4） -13（4） -9（3） 0（4） N3A 31（4） 58（4） 51（4） -27（4） -12（3） -4（3） N4A 36（4） 59（5） 40（4） -16（4） -12（3） 1（3） C1A 44（5） 57（6） 41（5） -21（4） -16（4） 2（5） C2A 30（4） 65（6） 33（4） -26（4） -13（4） 12（4） C3A 61（6） 65（6） 48（6） -20（5） -28（5） 6（5） C4A 57（6） 55（6） 60（6） -29（5） -19（5） 18（5） C5A 54（6） 79（7） 48（5） -36（5） -27（5） 18（5） C6A 34（5） 59（6） 45（5） -26（4） -15（4） 13（4） C7A 35（5） 72（6） 47（5） -34（5） -13（4） 5（5） C8A 32（4） 46（5） 30（4） -10（4） -12（4） 6（4） C9A 33（5） 61（6） 48（5） -18（4） -16（4） 5（4） C10A 38（5） 59（6） 46（5） -17（4） -18（4） -5（4） C11A 30（5） 59（6） 38（5） -14（4） -8（4） -1（4） C12A 31（4） 47（5） 34（4） -9（4） -10（4） 3（4） C13A 39（5） 91（7） 41（5） -34（5） -10（4） 12（5） C14A 36（5） 73（6） 46（5） -31（5） -12（4） 5（4） C15A 64（7） 81（8） 78（8） -44（6） -22（6） 6（6） C16A 58（6） 96（8） 39（5） -21（5） -25（5） 16（6） O3S 113（8） 120（8） 98（7） -25（6） -37（6） 19（7） [表 6-3 ]：組成物 4A 的鍵長（單位為Å）。 [表 6-4 ]：組成物 4A 的鍵角。原子原子原子角度 /^° C5C O1C C1C 116.5（6） C12C O3C C2C 117.1（7） O1C C1C C2C 105.3（6） O1C C1C C3C 108.6（7） C3C C1C C2C 111.5（7） O3C C2C C1C 106.6（6） O3C C2C C4C 108.9（6） C1C C2C C4C 110.9（7） O5C C3C C1C 109.9（7） O6C C3C O5C 126.1（8） O6C C3C C1C 124.0（8） O7C C4C O8C 127.3（8） O7C C4C C2C 122.3（8） O8C C4C C2C 110.4（7） O1C C5C C6C 110.8（8） O2C C5C O1C 124.1（8） O2C C5C C6C 125.1（8） C7C C6C C5C 119.6（9） C11C C6C C5C 121.9（9） C11C C6C C7C 118.1（10） C8C C7C C6C 122.4（12） C9C C8C C7C 119.1（13） C10C C9C C8C 120.6（12） C9C C10C C11C 119.5（13） C6C C11C C10C 119.7（12） O3C C12C C13C 112.4（8） O4C C12C O3C 122.7（8） O4C C12C C13C 124.9（8） C14C C13C C12C 120.6（9） C18C C13C C12C 120.4（9） C18C C13C C14C 118.8（10） C15C C14C C13C 120.1（10） C16C C15C C14C 120.5（10） C15C C16C C17C 118.7（12） C16C C17C C18C 120.4（14） C13C C18C C17C 120.5（12） C1B N1B C8B 115.5（7） C2B N1B C1B 121.7（7） C2B N1B C8B 122.6（7） C3B N2B C2B 116.6（7） C1B N3B C7B 126.9（8） C12B N4B C11B 118.8（8） O1B C1B N1B 121.2（8） O1B C1B N3B 122.4（9） N3B C1B N1B 116.3（8） N1B C2B C6B 119.7（8） N2B C2B N1B 117.3（7） N2B C2B C6B 123.1（8） N2B C3B Cl1B 116.9（7） N2B C3B C4B 125.0（8） C4B C3B Cl1B 118.0（7） F1B C4B C3B 121.5（8） F1B C4B C5B 120.2（8） C5B C4B C3B 118.3（8） C4B C5B C6B 119.2（8） C2B C6B C7B 120.9（8） C5B C6B C2B 117.7（8） C5B C6B C7B 121.2（8） O2B C7B N3B 121.3（9） O2B C7B C6B 124.9（9） N3B C7B C6B 113.8（7） C9B C8B N1B 118.0（7） C12B C8B N1B 120.2（7） C12B C8B C9B 121.7（7） C8B C9B C13B 121.4（8） C10B C9B C8B 116.6（8） C10B C9B C13B 122.0（8） C11B C10B C9B 119.9（8） N4B C11B C10B 123.0（8） N4B C12B C8B 119.9（8） N4B C12B C14B 116.2（7） C8B C12B C14B 123.8（7） C12B C14B C15B 113.0（8） C12B C14B C16B 110.5（8） C15B C14B C16B 111.7（9） C1A N1A C2A 121.5（7） C1A N1A C8A 118.9（7） C2A N1A C8A 119.5（7） C3A N2A C2A 116.6（8） C7A N3A C1A 126.9（8） C12A N4A C11A 120.6（7） O1A C1A N1A 120.7（8） O1A C1A N3A 122.4（8） N3A C1A N1A 116.9（8） N2A C2A N1A 116.6（7） N2A C2A C6A 124.3（8） C6A C2A N1A 119.1（8） N2A C3A Cl1A 116.6（7） N2A C3A C4A 123.7（9） C4A C3A Cl1A 119.7（8） F1A C4A C3A 119.7（9） C5A C4A F1A 121.1（9） C5A C4A C3A 119.2（9） C4A C5A C6A 119.7（9） C2A C6A C5A 116.4（9） C2A C6A C7A 121.0（8） C5A C6A C7A 122.6（8） O2A C7A N3A 120.9（9） O2A C7A C6A 124.4（9） N3A C7A C6A 114.7（8） C9A C8A N1A 118.0（7） C9A C8A C12A 122.2（7） C12A C8A N1A 119.7（7） C8A C9A C10A 115.9（8） C8A C9A C13A 123.3（8） C10A C9A C13A 120.7（8） C11A C10A C9A 119.5（8） C10A C11A N4A 123.5（8） N4A C12A C8A 118.2（8） N4A C12A C14A 118.8（7） C8A C12A C14A 123.0（7） C12A C14A C15A 110.2（8） C12A C14A C16A 109.8（8） C15A C14A C16A 111.6（9） C15S O3S C12S 101.0（16） O3S C12S C11S 98（2） C11T C12S O3S 114（3） C13S C12S O3S 101（3） C13S C12S C11T 119（4） C13T C12S O3S 108（3） C13T C12S C11S 124（4） C12S C13S C14S 94（3） C12S C13T C14S 106（3） C15S C14S C13S 105（2） C15S C14S C13T 98（2） C14S C15S O3S 109.6（18） C7S O2S C10S 109.8（17） O2S C7S C8S 98（2） C6S C7S O2S 110（2） C6S C7S C8S 105（2） C7S C8S C9S 108（3） C10S C9S C8S 104（3） C9S C10S O2S 110（2） C5S O1S C2S 99.3（14） O1S C2S C1S 115.3（16） O1S C2S C3S 109.3（14） C1S C2S C3S 113.3（18） C2S C3S C4S 102.4（19） C3S C4S C5S 100（2） O1S C5S C4S 110（2） [表 6-5 ]：組成物 4A 的氫分數原子座標（×10⁴ ）及等效各向同性位移參數（Å² × 10³ ）。U_eq 定義為正交U_ij 的跡線的1/3。原子 x y z U_eq H5C 2738 5676 7079 75 H8C 7257 4612 3523 74 H1C 5642 5286 5648 49 H2C 4246 5000 4813 47 H7C 8030 3133 7918 117 H8CA 8829 1329 8674 113 H9C 8046 -520 8781 129 H10C 6325 -589 8302 117 H11C 5582 1286 7440 113 H14C 824 2153 5456 67 H15C -125 131 6310 90 H16C 854 -1479 7197 118 H17C 2922 -1070 6936 117 H18C 3724 966 6375 104 H3B 6442 7830 7268 59 H5B 4284 3988 9467 59 H10B 10491 6619 10136 58 H11B 12147 6175 8883 53 H13A 7637 7233 9947 82 H13B 8351 6990 10789 82 H13C 7521 5873 10864 82 H14B 9141 5177 7246 64 H15A 11415 4105 7168 98 H15B 10492 3806 6645 98 H15D 10055 3410 7957 98 H16A 10303 7074 5885 109 H16B 10596 6013 5392 109 H16D 11573 6448 5797 109 H3A 14191 5912 1268 55 H5A 14875 1914 3171 65 H10A 9147 3010 831 57 H11A 7601 3622 2016 54 H13D 12178 3715 8 83 H13E 11236 2674 104 83 H13F 11970 2347 938 83 H14A 10773 4660 3501 60 H15E 9817 6386 3737 106 H15F 8738 6107 3360 106 H15G 10127 6543 2480 106 H16E 8174 3966 4816 96 H16F 9227 4126 5267 96 H16G 9198 3006 4874 96 H11D 403 121 11721 212 H11E -600 -1054 12212 212 H11F -968 318 11703 212 H11G -1060 -259 11882 290 H11H -1114 -1599 11825 290 H11I -1750 -509 11154 290 H12S 128 -753 9931 215 H12A -557 -686 10345 215 H13G 1497 -1393 10872 182 H13H 1451 -115 11089 182 H13I 1087 -1267 9548 182 H13J 1458 -1412 10592 182 H14D 3019 696 9168 186 H14E 2460 -284 8839 186 H14F 2628 537 9673 186 H14G 2896 104 8645 186 H15H 1338 997 8243 167 H15I 1947 1996 8512 167 H6SA 6575 -2283 5108 218 H6SB 5393 -1922 4756 218 H6SC 5233 -2417 6034 218 H7S 5282 -222 5136 186 H8SA 7003 307 3490 290 H8SB 7680 -861 4007 290 H9SA 8880 527 4152 184 H9SB 7923 1561 4003 184 H10D 7155 1055 5667 243 H10E 8144 66 5812 243 H1SA 6626 7716 2249 264 H1SB 5541 8496 2685 264 H1SC 6226 8839 1383 264 H2S 5277 6457 2441 126 H3SA 3789 7506 3528 175 H3SB 3293 6455 3231 175 H4SA 3168 9048 2302 249 H4SB 2364 7965 2275 249 H5SA 3745 8410 500 195 H5SB 4689 9246 647 195 [表 6-4 ]：組成物 4A 的氫鍵資訊。 D H A d （ D-H ） /Å d （ H-A ） /Å d （ D-A ） /Å D-H-A/ 度 O5C H5C N4B¹ 0.84 1.82 2.656（9） 170.9 O8C H8C N4A 0.84 1.79 2.624（9） 171.6 N3B H3B O2S² 0.88 1.94 2.805（12） 168.1 C14B H14B N1B 1.00 2.44 2.937（12） 110.1 N3A H3A O1S³ 0.88 1.95 2.798（12） 160.7 ––––¹ -1+x,+y,+z;² +x,1+y,+z;³ 1+x,+y,+z [表 6-5 ]：組成物 4A 中未完全佔有的所有原子的原子佔有率。原子 佔有率 C11S 0.5 H11D 0.5 H11E 0.5 H11F 0.5 C11T 0.5 H11G 0.5 H11H 0.5 H11I 0.5 H12S 0.5 H12A 0.5 C13S 0.5 H13G 0.5 H13H 0.5 C13T 0.5 H13I 0.5 H13J 0.5 H14D 0.5 H14E 0.5 H14F 0.5 H14G 0.5 Crystal data. C ₆₅ H ₇₂ Cl ₂ F ₂ N ₈ O ₁₅ , _Mr = 1314.20, triclinic, P 1 （No. 1）, a = 11.5683（10） Å, b = 11.6705（10） Å, c = 13.9593（12） Å, α = 68.1780（10） ^° , β = 69.4150（10） ^° , γ = 87.7760（10） ^° , V = 1628.7（2） Å ³ , T = 173（2） K, Z = 1, Z' = 1, μ （MoK _α ） = 0.178, 26758 reflections were measured, 11949 unique reflections ( R _int = 0.0528) was used for all calculations. The final wR ₂ was 0.2465 (all data), and R ₁ was 0.0835 (I > 2(I)). p [ Table 6-2 ]: Fractional atomic coordinates (×10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of composition 4A . U _eq is defined as 1/3 of the trace of the orthogonal U _ij . atom x y z U _eq O1C 5607 (5) 3451 (5) 6493 (5) 44.9 (14) O2C 6723 (6) 4580 (6) 6921 (5) 49.9 (15) O3C 3704 (5) 3216 (6) 5826 (5) 45.6 (14) O4C 2800 (6) 3841 (6) 4560 (6) 55.9 (16) O5C 3369 (5) 5630 (6) 6567 (5) 50.2 (15) O6C 3636 (5) 3990 (6) 7917 (5) 50.8 (15) 7C 5703 (6) 2984 (7) 4257 (5) 55.4 (16) 8C 6595 (5) 4867 (6) 3832 (5) 49.1 (15) C1C 5032 (7) 4527 (8) 6031 (7) 41 (2) C2C 4615 (7) 4267 (8) 5203 (7) 39.1 (19) C3C 3928 (8) 4667 (8) 6968 (7) 42 (2) C4C 5705 (8) 3954 (9) 4361 (7) 42 (2) C5C 6393 (8) 3601 (8) 6961 (7) 42 (2) C6C 6820 (9) 2403 (8) 7493 (8) 49 (2) C7C 7721 (15) 2378 (12) 7941 (13) 98 (3) C8C 8179 (15) 1311 (13) 8410 (13) 94 (3) C9C 7697 (17) 223 (14) 8497 (14) 107 (5) C10C 6708 (16) 185 (12) 8178 (13) 98 (3) C11C 6265 (15) 1303 (12) 7665 (13) 94 (3) C12C 2953 (8) 3028 (9) 5341 (7) 44 (2) C13C 2359 (9) 1762 (9) 5860 (8) 54 (2) C14C 1223 (9) 1501 (10) 5822 (8) 56 (2) C15C 671 (11) 300 (12) 6312 (10) 75 (3) C16C 1261 (14) -658 (13) 6805 (13) 98 (5) C17C 2446 (14) -407 (13) 6720 (13) 97 (4) C18C 2954 (13) 800 (12) 6325 (12) 87 (4) Cl1B 6935 (2) 1601 (2) 11106 (2) 66.0 (7) F1B 4643 (5) 1859 (6) 10647 (5) 66.7 (16) O1B 8509 (6) 7968 (6) 7303 (6) 58.0 (17) O2B 4575 (6) 6378 (7) 8234 (6) 66.1 (19) N1B 7896 (6) 6005 (6) 8607 (6) 40.4 (16) N2B 7345 (6) 3931 (7) 9798 (6) 42.2 (17) N3B 6567 (7) 7139 (7) 7745 (6) 49.2 (18) N4B 11242 (6) 5811 (7) 8040 (6) 47.4 (18) C1B 7710 (8) 7096 (9) 7832 (8) 48 (2) C2B 7030 (8) 4974 (8) 9152 (6) 40 (2) C3B 6537 (8) 2952 (9) 10275 (7) 47 (2) C4B 5411 (8) 2909 (8) 10151 (7) 47 (2) C5B 5070 (8) 3977 (10) 9543 (7) 49 (2) C6B 5884 (8) 5054 (9) 9031 (7) 44 (2) C7B 5584 (8) 6210 (9) 8328 (8) 50 (2) C8B 9103 (7) 5996 (7) 8717 (7) 41 (2) C9B 9205 (8) 6331 (8) 9550 (7) 43 (2) C10B 10370 (9) 6393 (9) 9588 (7) 49 (2) C11B 11350 (8) 6131 (8) 8840 (7) 44 (2) C12B 10113 (7) 5734 (7) 7981 (7) 38.9 (19) C13B 8078 (9) 6634 (9) 10360 (8) 55 (2) C14B 10040 (9) 5292 (9) 7127 (8) 54 (2) C15B 10546 (10) 4041 (10) 7234 (10) 65 (3) C16B 10688 (11) 6301 (12) 5939 (9) 73 (3) Cl1A 11316 (3) -588 (3) 4003 (3) 82.7 (9) F1A 13799 (6) -251 (6) 4033 (5) 77.9 (18) O1A 12158 (6) 6025 (6) 1115 (6) 57.3 (17) O2A 15430 (6) 4363 (7) 1981 (6) 63.4 (18) N1A 11949 (6) 3944 (6) 2039 (6) 38.9 (16) N2A 11735 (7) 1804 (7) 3004 (6) 48.6 (19) N3A 13776 (6) 5170 (7) 1580 (6) 45.5 (18) N4A 8608 (6) 4153 (7) 2689 (6) 46.4 (18) C1A 12607 (8) 5110 (9) 1551 (7) 47 (2) C2A 12449 (7) 2876 (8) 2555 (7) 40 (2) C3A 12216 (10) 797 (10) 3464 (8) 56 (2) C4A 13389 (10) 813 (9) 3546 (8) 56 (3) C5A 14083 (9) 1886 (10) 3114 (8) 54 (2) C6A 13638 (8) 2995 (8) 2564 (7) 44 (2) C7A 14365 (8) 4199 (9) 2043 (8) 48 (2) C8A 10709 (7) 3834 (8) 2039 (6) 37.4 (19) C9A 10540 (8) 3371 (9) 1305 (8) 47 (2) C10A 9326 (8) 3313 (8) 1314 (7) 47 (2) C11A 8421 (8) 3689 (8) 2008 (7) 45 (2) C12A 9733 (7) 4227 (7) 2738 (7) 39.4 (19) C13A 11568 (8) 2995 (10) 522 (8) 55 (2) C14A 9890 (8) 4703 (9) 3549 (7) 50 (2) C15A 9619 (11) 6056 (11) 3255 (11) 71 (3) C16A 9045 (10) 3875 (11) 4734 (8) 64 (3) O3S 355 (10) 1070 (10) 9718 (9) 116 (3) C11S -300 (40) -220 (40) 11630 (40) 142 (14) C11T -1050 (40) -700 (50) 11410 (40) 190 (20) C12S 160 (30) -310 (30) 10410 (20) 180 (9) C13S 1360 (40) -510 (50) 10600 (40) 151 (11) C13T 1220 (40) -820 (40) 9990 (40) 151 (11) C14S 2240 (20) 280 (20) 9240 (20) 155 (8) C15S 1510 (20) 1150 (20) 8834 (18) 139 (7) O2S 6461 (8) -721 (8) 5995 (7) 83 (2) C6S 5780 (20) -1920 (20) 5275 (19) 145 (7) C7S 6000 (20) -720 (20) 5170 (20) 155 (8) C8S 7200 (30) -180 (30) 4150 (30) 241 (15) C9S 7990 (20) 670 (20) 4390 (20) 153 (7) C10S 7490 (30) 340 (30) 5490 (30) 202 (11) O1S 4966 (9) 7468 (9) 1097 (8) 99 (3) C1S 5930 (20) 8160 (20) 2110 (20) 176 (9) C2S 5018 (15) 7306 (16) 2147 (14) 105 (5) C3S 3770 (20) 7280 (20) 2920 (20) 146 (7) C4S 3200 (30) 8270 (30) 2170 (30) 207 (12) C5S 4180 (20) 8430 (20) 990 (20) 162 (8) [ Table 6-3 ]: Anisotropic displacement parameters (×10 ⁴ ) of composition 4A . The anisotropic displacement factor index is in the following form: -2π ² [h ² a* ² × U ₁₁ + ... +2hka* × b* × U ₁₂ ]$ atom U ₁₁ U ₂₂ U ₃₃ U ₂₃ U ₁₃ U ₁₂ O1C 37 (3) 57 (4) 52 (3) -27 (3) -25 (3) 9 (3) O2C 47 (4) 54 (4) 52 (4) -21 (3) -21 (3) 4 (3) O3C 33 (3) 63 (4) 39 (3) -21 (3) -10 (3) -3 (3) O4C 52 (4) 68 (4) 53 (4) -20 (4) -26 (3) 1 (3) O5C 34 (3) 56 (4) 53 (4) -19 (3) -11 (3) 9 (3) O6C 44 (3) 71 (4) 35 (4) -21 (3) -11 (3) 3 (3) 7C 46 (4) 71 (5) 56 (4) -34 (4) -15 (3) 3 (3) 8C 33 (3) 56 (4) 55 (4) -22 (3) -11 (3) 7 (3) C1C 31 (4) 48 (5) 47 (5) -20 (4) -14 (4) 1 (4) C2C 35 (5) 42 (5) 41 (5) -16 (4) -14 (4) 2 (4) C3C 37 (5) 52 (5) 39 (5) -21 (4) -14 (4) 2 (4) C4C 36 (5) 51 (5) 45 (5) -17 (4) -22 (4) 6 (4) C5C 40 (5) 48 (5) 35 (4) -16 (4) -11 (4) 5 (4) C6C 58 (6) 45 (5) 51 (5) -22 (4) -26 (5) 10 (4) C7C 141 (9) 68 (6) 117 (8) -37 (6) -85 (8) 23 (6) C8C 124 (9) 77 (6) 120 (8) -41 (6) -86 (7) 41 (6) C9C 155 (14) 87 (10) 133 (13) -53 (9) -107 (12) 68 (10) C10C 141 (9) 68 (6) 117 (8) -37 (6) -85 (8) 23 (6) C11C 124 (9) 77 (6) 120 (8) -41 (6) -86 (7) 41 (6) C12C 35 (5) 65 (6) 38 (5) -26 (5) -15 (4) 3 (4) C13C 50 (6) 59 (6) 56 (6) -23 (5) -23 (5) 6 (5) C14C 47 (6) 71 (7) 58 (6) -31 (5) -22 (5) 1 (5) C15C 54 (6) 101 (10) 73 (8) -34 (7) -22 (6) -21 (6) C16C 96 (10) 81 (9) 114 (11) -3 (8) -67 (9) -27 (8) C17C 98 (10) 73 (8) 110 (11) -10 (8) -51 (9) -2 (7) C18C 88 (9) 77 (8) 102 (10) -20 (7) -56 (8) -9 (7) Cl1B 67.9 (16) 57.4 (14) 64.2 (16) -10.1 (12) -27.3 (13) -6.4 (12) F1B 67 (4) 76 (4) 55 (3) -19 (3) -22 (3) -23 (3) O1B 41 (4) 55 (4) 71 (4) -12 (3) -23 (3) -6 (3) O2B 36 (4) 89 (5) 78 (5) -31 (4) -28 (3) 11 (3) N1B 23 (3) 42 (4) 51 (4) -12 (3) -13 (3) -6 (3) N2B 33 (4) 54 (5) 35 (4) -14 (3) -10 (3) -5 (3) N3B 40 (4) 58 (5) 48 (4) -12 (4) -23 (4) 2 (4) N4B 35 (4) 47 (4) 59 (5) -17 (4) -18 (4) 7 (3) C1B 38 (5) 55 (6) 58 (6) -27 (5) -22 (4) 9 (5) C2B 37 (5) 53 (5) 27 (4) -15 (4) -9 (4) 1 (4) C3B 46 (5) 55 (6) 40 (5) -19 (4) -14 (4) 6 (4) C4B 49 (5) 54 (6) 36 (5) -16 (4) -14 (4) -12 (4) C5B 29 (5) 83 (7) 35 (5) -25 (5) -9 (4) -6 (5) C6B 32 (5) 64 (6) 37 (5) -21 (4) -10 (4) -8 (4) C7B 38 (5) 67 (6) 50 (5) -23 (5) -19 (4) 3 (4) C8B 34 (5) 43 (5) 48 (5) -15 (4) -19 (4) 2 (4) C9B 39 (5) 51 (5) 42 (5) -22 (4) -12 (4) 1 (4) C10B 49 (6) 59 (6) 42 (5) -20 (4) -20 (4) 10 (4) C11B 42 (5) 50 (5) 46 (5) -17 (4) -23 (4) 4 (4) C12B 28 (4) 42 (5) 47 (5) -17 (4) -14 (4) 2 (3) C13B 44 (5) 62 (6) 52 (6) -25 (5) -8 (4) 7 (5) C14B 40 (5) 62 (6) 61 (6) -26 (5) -18 (5) 0 (4) C15B 52 (6) 72 (7) 89 (8) -52 (6) -22 (6) 7 (5) C16B 66 (7) 99 (9) 50 (6) -23 (6) -21 (5) -10 (6) Cl1A 84 (2) 60.8 (16) 85 (2) -4.6 (15) -34.1 (16) -3.2 (14) F1A 89 (5) 73 (4) 76 (4) -21 (3) -45 (4) 31 (3) O1A 45 (4) 60 (4) 64 (4) -17 (4) -23 (3) 1 (3) O2A 42 (4) 87 (5) 76 (5) -38 (4) -33 (3) 8 (3) N1A 26 (3) 53 (4) 37 (4) -16 (3) -12 (3) 1 (3) N2A 41 (4) 59 (5) 37 (4) -13 (4) -9 (3) 0 (4) N3A 31 (4) 58 (4) 51 (4) -27 (4) -12 (3) -4 (3) N4A 36 (4) 59 (5) 40 (4) -16 (4) -12 (3) 1 (3) C1A 44 (5) 57 (6) 41 (5) -21 (4) -16 (4) 2 (5) C2A 30 (4) 65 (6) 33 (4) -26 (4) -13 (4) 12 (4) C3A 61 (6) 65 (6) 48 (6) -20 (5) -28 (5) 6 (5) C4A 57 (6) 55 (6) 60 (6) -29 (5) -19 (5) 18 (5) C5A 54 (6) 79 (7) 48 (5) -36 (5) -27 (5) 18 (5) C6A 34 (5) 59 (6) 45 (5) -26 (4) -15 (4) 13 (4) C7A 35 (5) 72 (6) 47 (5) -34 (5) -13 (4) 5 (5) C8A 32 (4) 46 (5) 30 (4) -10 (4) -12 (4) 6 (4) C9A 33 (5) 61 (6) 48 (5) -18 (4) -16 (4) 5 (4) C10A 38 (5) 59 (6) 46 (5) -17 (4) -18 (4) -5 (4) C11A 30 (5) 59 (6) 38 (5) -14 (4) -8 (4) -1 (4) C12A 31 (4) 47 (5) 34 (4) -9 (4) -10 (4) 3 (4) C13A 39 (5) 91 (7) 41 (5) -34 (5) -10 (4) 12 (5) C14A 36 (5) 73 (6) 46 (5) -31 (5) -12 (4) 5 (4) C15A 64 (7) 81 (8) 78 (8) -44 (6) -22 (6) 6 (6) C16A 58 (6) 96 (8) 39 (5) -21 (5) -25 (5) 16 (6) O3S 113 (8) 120 (8) 98 (7) -25 (6) -37 (6) 19 (7) [ Table 6-3 ]: Bond lengths of component 4A (in Å). [ Table 6-4 ]: Key angles of composition 4A . atom atom atom Angle / ^° C5C O1C C1C 116.5 (6) C12C O3C C2C 117.1 (7) O1C C1C C2C 105.3 (6) O1C C1C C3C 108.6 (7) C3C C1C C2C 111.5 (7) O3C C2C C1C 106.6 (6) O3C C2C C4C 108.9 (6) C1C C2C C4C 110.9 (7) O5C C3C C1C 109.9 (7) O6C C3C O5C 126.1 (8) O6C C3C C1C 124.0 (8) 7C C4C 8C 127.3 (8) 7C C4C C2C 122.3 (8) 8C C4C C2C 110.4 (7) O1C C5C C6C 110.8 (8) O2C C5C O1C 124.1 (8) O2C C5C C6C 125.1 (8) C7C C6C C5C 119.6 (9) C11C C6C C5C 121.9 (9) C11C C6C C7C 118.1 (10) C8C C7C C6C 122.4 (12) C9C C8C C7C 119.1 (13) C10C C9C C8C 120.6 (12) C9C C10C C11C 119.5 (13) C6C C11C C10C 119.7 (12) O3C C12C C13C 112.4 (8) O4C C12C O3C 122.7 (8) O4C C12C C13C 124.9 (8) C14C C13C C12C 120.6 (9) C18C C13C C12C 120.4 (9) C18C C13C C14C 118.8 (10) C15C C14C C13C 120.1 (10) C16C C15C C14C 120.5 (10) C15C C16C C17C 118.7 (12) C16C C17C C18C 120.4 (14) C13C C18C C17C 120.5 (12) C1B N1B C8B 115.5 (7) C2B N1B C1B 121.7 (7) C2B N1B C8B 122.6 (7) C3B N2B C2B 116.6 (7) C1B N3B C7B 126.9 (8) C12B N4B C11B 118.8 (8) O1B C1B N1B 121.2 (8) O1B C1B N3B 122.4 (9) N3B C1B N1B 116.3 (8) N1B C2B C6B 119.7 (8) N2B C2B N1B 117.3 (7) N2B C2B C6B 123.1 (8) N2B C3B Cl1B 116.9 (7) N2B C3B C4B 125.0 (8) C4B C3B Cl1B 118.0 (7) F1B C4B C3B 121.5 (8) F1B C4B C5B 120.2 (8) C5B C4B C3B 118.3 (8) C4B C5B C6B 119.2 (8) C2B C6B C7B 120.9 (8) C5B C6B C2B 117.7 (8) C5B C6B C7B 121.2 (8) O2B C7B N3B 121.3 (9) O2B C7B C6B 124.9 (9) N3B C7B C6B 113.8 (7) C9B C8B N1B 118.0 (7) C12B C8B N1B 120.2 (7) C12B C8B C9B 121.7 (7) C8B C9B C13B 121.4 (8) C10B C9B C8B 116.6 (8) C10B C9B C13B 122.0 (8) C11B C10B C9B 119.9 (8) N4B C11B C10B 123.0 (8) N4B C12B C8B 119.9 (8) N4B C12B C14B 116.2 (7) C8B C12B C14B 123.8 (7) C12B C14B C15B 113.0 (8) C12B C14B C16B 110.5 (8) C15B C14B C16B 111.7 (9) C1A N1A C2A 121.5 (7) C1A N1A C8A 118.9 (7) C2A N1A C8A 119.5 (7) C3A N2A C2A 116.6 (8) C7A N3A C1A 126.9 (8) C12A N4A C11A 120.6 (7) O1A C1A N1A 120.7 (8) O1A C1A N3A 122.4 (8) N3A C1A N1A 116.9 (8) N2A C2A N1A 116.6 (7) N2A C2A C6A 124.3 (8) C6A C2A N1A 119.1 (8) N2A C3A Cl1A 116.6 (7) N2A C3A C4A 123.7 (9) C4A C3A Cl1A 119.7 (8) F1A C4A C3A 119.7 (9) C5A C4A F1A 121.1 (9) C5A C4A C3A 119.2 (9) C4A C5A C6A 119.7 (9) C2A C6A C5A 116.4 (9) C2A C6A C7A 121.0 (8) C5A C6A C7A 122.6 (8) O2A C7A N3A 120.9 (9) O2A C7A C6A 124.4 (9) N3A C7A C6A 114.7 (8) C9A C8A N1A 118.0 (7) C9A C8A C12A 122.2 (7) C12A C8A N1A 119.7 (7) C8A C9A C10A 115.9 (8) C8A C9A C13A 123.3 (8) C10A C9A C13A 120.7 (8) C11A C10A C9A 119.5 (8) C10A C11A N4A 123.5 (8) N4A C12A C8A 118.2 (8) N4A C12A C14A 118.8 (7) C8A C12A C14A 123.0 (7) C12A C14A C15A 110.2 (8) C12A C14A C16A 109.8 (8) C15A C14A C16A 111.6 (9) C15S O3S C12S 101.0 (16) O3S C12S C11S 98 (2) C11T C12S O3S 114 (3) C13S C12S O3S 101 (3) C13S C12S C11T 119 (4) C13T C12S O3S 108 (3) C13T C12S C11S 124 (4) C12S C13S C14S 94 (3) C12S C13T C14S 106 (3) C15S C14S C13S 105 (2) C15S C14S C13T 98 (2) C14S C15S O3S 109.6 (18) C7S O2S C10S 109.8 (17) O2S C7S C8S 98 (2) C6S C7S O2S 110 (2) C6S C7S C8S 105 (2) C7S C8S C9S 108 (3) C10S C9S C8S 104 (3) C9S C10S O2S 110 (2) C5S O1S C2S 99.3 (14) O1S C2S C1S 115.3 (16) O1S C2S C3S 109.3 (14) C1S C2S C3S 113.3 (18) C2S C3S C4S 102.4 (19) C3S C4S C5S 100 (2) O1S C5S C4S 110 (2) [ Table 6-5 ]: Atomic coordinates (×10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of the hydrogen fraction of composition 4A . U _eq is defined as 1/3 of the trace of the orthogonal U _ij . atom x y z U _eq H5C 2738 5676 7079 75 H8C 7257 4612 3523 74 H1C 5642 5286 5648 49 H2C 4246 5000 4813 47 H7C 8030 3133 7918 117 H8CA 8829 1329 8674 113 H9C 8046 -520 8781 129 H10C 6325 -589 8302 117 H11C 5582 1286 7440 113 H14C 824 2153 5456 67 H15C -125 131 6310 90 H16C 854 -1479 7197 118 H17C 2922 -1070 6936 117 H18C 3724 966 6375 104 H3B 6442 7830 7268 59 H5B 4284 3988 9467 59 H10B 10491 6619 10136 58 H11B 12147 6175 8883 53 H13A 7637 7233 9947 82 H13B 8351 6990 10789 82 H13C 7521 5873 10864 82 H14B 9141 5177 7246 64 H15A 11415 4105 7168 98 H15B 10492 3806 6645 98 H15D 10055 3410 7957 98 H16A 10303 7074 5885 109 H16B 10596 6013 5392 109 H16D 11573 6448 5797 109 H3A 14191 5912 1268 55 H5A 14875 1914 3171 65 H10A 9147 3010 831 57 H11A 7601 3622 2016 54 H13D 12178 3715 8 83 H13E 11236 2674 104 83 H13F 11970 2347 938 83 H14A 10773 4660 3501 60 H15E 9817 6386 3737 106 H15F 8738 6107 3360 106 H15G 10127 6543 2480 106 H16E 8174 3966 4816 96 H16F 9227 4126 5267 96 H16G 9198 3006 4874 96 H11D 403 121 11721 212 H11E -600 -1054 12212 212 H11F -968 318 11703 212 H11G -1060 -259 11882 290 H11H -1114 -1599 11825 290 H11I -1750 -509 11154 290 H12S 128 -753 9931 215 H12A -557 -686 10345 215 H13G 1497 -1393 10872 182 H13H 1451 -115 11089 182 H13I 1087 -1267 9548 182 H13J 1458 -1412 10592 182 H14D 3019 696 9168 186 H14E 2460 -284 8839 186 H14F 2628 537 9673 186 H14G 2896 104 8645 186 H15H 1338 997 8243 167 H15I 1947 1996 8512 167 H6SA 6575 -2283 5108 218 H6SB 5393 -1922 4756 218 H6SC 5233 -2417 6034 218 H7S 5282 -222 5136 186 H8SA 7003 307 3490 290 H8S 7680 -861 4007 290 H9SA 8880 527 4152 184 H9SB 7923 1561 4003 184 H10D 7155 1055 5667 243 H10E 8144 66 5812 243 H1SA 6626 7716 2249 264 H1SB 5541 8496 2685 264 H1SC 6226 8839 1383 264 H2S 5277 6457 2441 126 H3SA 3789 7506 3528 175 H3SB 3293 6455 3231 175 H4SA 3168 9048 2302 249 H4SB 2364 7965 2275 249 H5SA 3745 8410 500 195 H5SB 4689 9246 647 195 [ Table 6-4 ]: Hydrogen bonding information of composition 4A . D H A d ( DH ) /Å d ( HA ) /Å d ( DA ) /Å DHA/ degree O5C H5C N4B ¹ 0.84 1.82 2.656 (9) 170.9 8C H8C N4A 0.84 1.79 2.624 (9) 171.6 N3B H3B O2S ² 0.88 1.94 2.805 (12) 168.1 C14B H14B N1B 1.00 2.44 2.937 (12) 110.1 N3A H3A O1S ³ 0.88 1.95 2.798 (12) 160.7 –––– ¹ -1+x,+y,+z; ² +x,1+y,+z; ³ 1+x,+y,+z [ Table 6-5 ]: Atomic occupancy of all atoms that are not fully occupied in composition 4A . atom Occupancy rate C11S 0.5 H11D 0.5 H11E 0.5 H11F 0.5 C11T 0.5 H11G 0.5 H11H 0.5 H11I 0.5 H12S 0.5 H12A 0.5 C13S 0.5 H13G 0.5 H13H 0.5 C13T 0.5 H13I 0.5 H13J 0.5 H14D 0.5 H14E 0.5 H14F 0.5 H14G 0.5

前述內容僅是本發明的說明，並不旨在將本發明限制為所揭露的用途。對於熟習此項技術者而言係習知的變化及改變旨在落入由所附申請專利範圍限定的本發明的範圍及性質內。所有提及的參考文獻、專利、申請及出版物均藉由引用全文併入本文，就如同在此書寫一樣。The foregoing is merely illustrative of the present invention and is not intended to limit the present invention to the disclosed uses. Variations and modifications known to those skilled in the art are intended to fall within the scope and nature of the present invention as defined by the appended patent applications. All references, patents, applications, and publications mentioned are incorporated herein by reference in their entirety, as if written herein.

[圖1]顯示了組成物4a之晶體排列。[Figure 1] shows the crystal arrangement of composition 4a.

[圖2-1]顯示了A〜E型二酮型外消旋物之XRPD疊加圖。[Figure 2-1] shows the XRPD overlay of diketo racemates A to E.

[圖2-2]顯示了(1S)-(-)-樟腦酸共晶體之XRPD疊加圖。[Figure 2-2] shows the XRPD overlay pattern of (1S)-(-)-camphoric acid cocrystal.

[圖2-3]顯示了(+)-2, 3-二苯甲醯基-D-酒石酸共晶體之XRPD疊加圖。[Figure 2-3] shows the XRPD overlay pattern of (+)-2, 3-dibenzoyl-D-tartaric acid cocrystal.

[圖2-4]顯示了D-(+)-蘋果酸共晶體之XRPD疊加圖。[Figure 2-4] shows the XRPD overlay pattern of D-(+)-malic acid cocrystal.

[圖2-5]顯示了不同溫度下間二酮共晶體之XRPD疊加圖。[Figure 2-5] shows the XRPD overlay patterns of dione cocrystals at different temperatures.

[圖2-6]顯示了不同溫度下對二酮共晶體之XRPD疊加圖。[Figure 2-6] shows the XRPD overlay patterns of diketone cocrystals at different temperatures.

[圖2-7]顯示了不同溫度下間二酮共晶體及對二酮共晶體混合物之XRPD疊加圖。[Figure 2-7] shows the XRPD overlay patterns of meta-diketone cocrystals and para-diketone cocrystal mixtures at different temperatures.

[圖2-8]顯示了不同溫度下二酮外消旋物之XRPD疊加圖（I/II）。[Figure 2-8] shows the XRPD overlay patterns (I/II) of the diketone racemate at different temperatures.

[圖2-9]顯示了不同溫度下二酮外消旋物之XRPD疊加圖（II/II）。[Figure 2-9] shows the XRPD overlay patterns (II/II) of the diketone racemate at different temperatures.

[圖2-10]顯示了間/對-二酮共晶體之三元相圖。[Figure 2-10] shows the ternary phase diagram of the m/p-diketone eutectic.

[圖2-11]顯示了間/對-二酮之三元相圖。[Figure 2-11] shows the ternary phase diagram of m/p-diketone.

[圖3-1]顯示了A型二酮外消旋物之XRPD。[Figure 3-1] shows the XRPD of diketone racemate type A.

[圖3-2]顯示了A型二酮外消旋物之TGA/DSC疊加圖。[Figure 3-2] shows the TGA/DSC overlay of the type A diketone racemate.

[圖3-3]顯示了A型二酮外消旋物之¹ H NMR譜圖。[Figure 3-3] shows the ¹ H NMR spectrum of the type A diketone racemate.

[圖3-4]顯示了A型二酮外消旋物之PLM圖像。[Figure 3-4] shows the PLM image of type A diketone racemate.

[圖3-5]顯示了B型二酮外消旋物之XRPD。[Figure 3-5] shows the XRPD of the type B diketone racemate.

[圖3-6]顯示了B型二酮外消旋物之TGA/DSC疊加圖。[Figure 3-6] shows the TGA/DSC overlay of the Type B diketone racemate.

[圖3-7]顯示了B型二酮外消旋物之¹ H NMR譜圖。[Figure 3-7] shows the ¹ H NMR spectrum of the type B diketone racemate.

[圖3-8]顯示了C型二酮外消旋物之XRPD。[Figure 3-8] shows the XRPD of the C-type diketone racemate.

[圖3-9]顯示了C型二酮外消旋物之TGA/DSC疊加圖。[Figure 3-9] shows the TGA/DSC overlay of the C-type diketone racemate.

[圖3-10]顯示了C型二酮外消旋物之¹ H NMR譜圖。[Figure 3-10] shows the ¹ H NMR spectrum of the C-type diketone racemate.

[圖3-11]顯示了D型二酮外消旋物之XRPD。[Figure 3-11] shows the XRPD of the D-dione racemate.

[圖3-12]顯示了D型二酮外消旋物之TGA/DSC疊加圖。[Figure 3-12] shows the TGA/DSC overlay of the D-type diketone racemate.

[圖3-13]顯示了D型二酮外消旋物之¹ H NMR譜圖。[Figure 3-13] shows the ¹ H NMR spectrum of the D-type diketone racemate.

[圖3-14]顯示了E型二酮外消旋物之XRPD。[Figure 3-14] shows the XRPD of the E-type diketone racemate.

[圖3-15]顯示了E型二酮外消旋物之TGA/DSC疊加圖。[Figure 3-15] shows the TGA/DSC overlay of the E-type diketone racemate.

[圖3-16]顯示了E型二酮外消旋物之¹ H NMR譜圖。[Figure 3-16] shows the ¹ H NMR spectrum of the E-type diketone racemate.

[圖3-17]顯示了A型間二酮共晶體之XRPD。[Figure 3-17] shows the XRPD of type A meta-diketone cocrystal.

[圖3-18]顯示了A型間二酮共晶體之TGA/DSC疊加圖。[Figure 3-18] shows the TGA/DSC overlay of type A meta-diketone cocrystal.

[圖3-19]顯示了A型間二酮共晶體之¹ H NMR譜圖。[Figure 3-19] shows the ¹ H NMR spectrum of type A meta-diketone cocrystal.

[圖3-20]顯示了A型對二酮共晶體之XRPD。[Figure 3-20] shows the XRPD of type A para-diketone cocrystal.

[圖3-21]顯示了A型對二酮共晶體之TGA/DSC疊加圖。[Figure 3-21] shows the TGA/DSC overlay of type A para-diketone cocrystal.

[圖3-22]顯示了A型對二酮共晶體之¹ H NMR譜圖。[Figure 3-22] shows the ¹ H NMR spectrum of type A para-diketone cocrystal.

[圖3-23]顯示了二酮外消旋物形式之XRPD疊加圖。[Figure 3-23] shows the XRPD overlay of the diketone racemate form.

[圖3-24]顯示了競爭性漿液樣本之XRPD。[Figure 3-24] shows the XRPD of the competitive plasma sample.

[圖3-25]顯示了製備之對二酮共晶體之XRPD疊加圖。[Figure 3-25] shows the XRPD overlay of the prepared p-diketone cocrystal.

[圖3-26]顯示了間/對-二酮共晶體之¹ H NMR譜圖疊加圖。[Figure 3-26] shows the overlay of ¹ H NMR spectra of m/p-diketone cocrystal.

[圖3-27]顯示了製備之對二酮共晶體之XRPD疊加圖。[Figure 3-27] shows the XRPD overlay pattern of the prepared p-diketone cocrystal.

[圖4-1]顯示了間二酮DBTA共晶體形式之相互轉換圖。[Figure 4-1] shows the interconversion diagram of the dione DBTA cocrystal forms.

[圖5-1]顯示了間二酮DBTA共晶體形式（A〜E型）之XRPD疊加圖。[Figure 5-1] shows the XRPD overlay of the dione DBTA cocrystal forms (types A to E).

[圖5-2]顯示了間二酮DBTA共晶體形式（F〜K型）之XRPD疊加圖。[Figure 5-2] shows the XRPD overlay of the dione DBTA cocrystal form (F~K form).

[圖5-3]顯示了間二酮DBTA共晶體形式（L〜Q型）之XRPD疊加圖。[Figure 5-3] shows the XRPD overlay pattern of the dione DBTA cocrystal form (L~Q form).

[圖5-4]顯示了A型之XRPD圖。[Figure 5-4] shows the XRPD pattern of type A.

[圖5-5]顯示了A型之TGA/DSC曲線。[Figure 5-5] shows the TGA/DSC curve of type A.

[圖5-6]顯示了A型之¹ H NMR。[Figure 5-6] shows the ¹ H NMR of type A.

[圖5-7]顯示了B型之XRPD疊加圖。[Figure 5-7] shows the XRPD overlay of Form B.

[圖5-8]顯示了B型之TGA/DSC曲線。[Figure 5-8] shows the TGA/DSC curve of type B.

[圖5-9]顯示了B型之¹ H NMR。[Figure 5-9] shows the ¹ H NMR of Form B.

[圖5-10]顯示了C型之XRPD圖。[Figure 5-10] shows the XRPD pattern of type C.

[圖5-11]顯示了C型之TGA/DSC曲線。[Figure 5-11] shows the TGA/DSC curve of type C.

[圖5-12]顯示了C型之¹ H NMR。[Figure 5-12] shows the ¹ H NMR of type C.

[圖5-13]顯示了D型之XRPD圖。[Figure 5-13] shows the XRPD pattern of type D.

[圖5-14]顯示了D型之TGA/DSC曲線。[Figure 5-14] shows the TGA/DSC curve of type D.

[圖5-15]顯示了D型之¹ H NMR。[Figure 5-15] shows the ¹ H NMR of the D-type.

[圖5-16]顯示了E型之XRPD圖。[Figure 5-16] shows the XRPD pattern of type E.

[圖5-17]顯示了E型之TGA/DSC曲線。[Figure 5-17] shows the TGA/DSC curve of type E.

[圖5-18]顯示了E型之¹ H NMR。[Figure 5-18] shows the ¹ H NMR of E type.

[圖5-19]顯示了F型之XRPD圖。[Figure 5-19] shows the XRPD pattern of type F.

[圖5-20]顯示了F型之TGA/DSC曲線。[Figure 5-20] shows the TGA/DSC curve of type F.

[圖5-21]顯示了F型之¹ H NMR。[Figure 5-21] shows the ¹ H NMR of type F.

[圖5-22]顯示了G型之XRPD圖。[Figure 5-22] shows the XRPD pattern of type G.

[圖5-23]顯示了G型之TGA/DSC曲線。[Figure 5-23] shows the TGA/DSC curve of type G.

[圖5-24]顯示了G型之¹ H NMR。[Figure 5-24] shows the ¹ H NMR of type G.

[圖5-25]顯示了H型之XRPD圖。[Figure 5-25] shows the XRPD pattern of type H.

[圖5-26]顯示了H型之TGA/DSC曲線。[Figure 5-26] shows the TGA/DSC curve of type H.

[圖5-27]顯示了H型之¹ H NMR。[Figure 5-27] shows the ¹ H NMR of the H type.

[圖5-28]顯示了I型之XRPD圖。[Figure 5-28] shows the XRPD pattern of Form I.

[圖5-29]顯示了I型之TGA/DSC曲線。[Figure 5-29] shows the TGA/DSC curve of type I.

[圖5-30]顯示了I型之¹ H NMR。[Figure 5-30] shows the ¹ H NMR of type I.

[圖5-31]顯示了J型之XRPD圖。[Figure 5-31] shows the XRPD pattern of type J.

[圖5-32]顯示了J型之TGA/DSC曲線。[Figure 5-32] shows the J-shaped TGA/DSC curve.

[圖5-33]顯示了J型之¹ H NMR。[Figure 5-33] shows the J-type ¹ H NMR.

[圖5-34]顯示了K型之XRPD圖。[Figure 5-34] shows the XRPD pattern of type K.

[圖5-35]顯示了K型之TGA/DSC曲線。[Figure 5-35] shows the TGA/DSC curve of type K.

[圖5-36]顯示了K型之¹ H NMR。[Figure 5-36] shows the ¹ H NMR of type K.

[圖5-37]顯示了L型之XRPD圖。[Figure 5-37] shows the XRPD pattern of L-type.

[圖5-38]顯示了L型之TGA/DSC曲線。[Figure 5-38] shows the L-type TGA/DSC curve.

[圖5-39]顯示了L型之¹ H NMR。[Figure 5-39] shows the ¹ H NMR of L-type.

[圖5-40]顯示了M型之XRPD圖。[Figure 5-40] shows the XRPD pattern of type M.

[圖5-41]顯示了M型之TGA/DSC曲線。[Figure 5-41] shows the TGA/DSC curve of type M.

[圖5-42]顯示了M型之¹ H NMR。[Figure 5-42] shows the M-type ¹ H NMR.

[圖5-43]顯示了N型之XRPD圖。[Figure 5-43] shows the XRPD pattern of type N.

[圖5-44]顯示了N型之TGA/DSC曲線。[Figure 5-44] shows the TGA/DSC curve of type N.

[圖5-45]顯示了N型之¹ H NMR。[Figure 5-45] shows the ¹ H NMR of N-type.

[圖5-46]顯示了O型之XRPD圖。[Figure 5-46] shows the XRPD pattern of type O.

[圖5-47]顯示了O型之TGA/DSC曲線。[Figure 5-47] shows the TGA/DSC curve of type O.

[圖5-48]顯示了O型之¹ H NMR。[Figure 5-48] shows the ¹ H NMR of the O form.

[圖5-49]顯示了P型之XRPD圖。[Figure 5-49] shows the XRPD pattern of type P.

[圖5-50]顯示了P型之TGA/DSC曲線。[Figure 5-50] shows the TGA/DSC curve of type P.

[圖5-51]顯示了P型之¹ H NMR。[Figure 5-51] shows the ¹ H NMR of P type.

[圖5-52]顯示了Q型之XRPD圖。[Figure 5-52] shows the XRPD pattern of type Q.

[圖5-53]顯示了Q型之TGA/DSC曲線。[Figure 5-53] shows the TGA/DSC curve of Q type.

[圖5-54]顯示了Q型之¹ H NMR。[Figure 5-54] shows the ¹ H NMR of Q type.

[圖6-1]顯示了用1,3-二苯基-3-側氧基丙磺酸拆分得到的M-5之HPLC。[Figure 6-1] shows the HPLC of M-5 obtained by separation with 1,3-diphenyl-3-hydroxypropanesulfonic acid.

[圖6-2]顯示了用1,3-二苯基-3-側氧基丙磺酸拆分得到的5（對-阻轉異構物過量）之HPLC。[Figure 6-2] shows the HPLC of 5 (excess p-atropisomer) obtained by resolution with 1,3-diphenyl-3-hydroxypropanesulfonic acid.

Claims

A composition comprising a compound having formula 4

and a compound having formula B

The composition of claim 1, wherein the compound of formula 4 is a compound of formula 5M:

The composition of claim 1, wherein the compound of formula 4 is a compound of formula 5P:

The composition of claim 2, wherein the compound having formula B is a compound having formula B1

The composition of claim 2, wherein the compound having formula B is a compound having formula B2

A composition as claimed in any one of claims 1 to 5, wherein the composition comprises a 2:1 ratio of the compound having formula 4 to the compound having formula B.

A composition as claimed in any one of claims 1 to 5, wherein the composition further comprises 2-methyltetrahydrofuran.

The composition of claim 7, wherein the ratio of the 2-methyltetrahydrofuran to the compound of formula B is 2:1.

The composition of claim 1, wherein the composition is

The composition of claim 9, wherein the composition is

The composition of claim 9, wherein the composition is

A composition as claimed in any one of claims 9 to 11, wherein the composition is in a crystalline state.

A composition as claimed in any one of claims 9 to 11, wherein the composition is a co-crystal.

A method for preparing a compound having formula 4,

It comprises mixing 2,6-dichloro-5-fluoro- N -{[4-methyl-2-(propan-2-yl)pyridin-3-yl]aminocarbonyl}pyridine-3-carboxamide with sodium tert-butoxide to form a compound having formula 4.

The method of claim 14, wherein 1 molar equivalent of the 2,6-dichloro-5-fluoro- N -{[4-methyl-2-(propan-2-yl)pyridin-3-yl]aminocarbonyl}pyridine-3-carboxamide is mixed with 2 molar equivalents of the sodium tert-butoxide.

A method as claimed in claim 14 or 15, wherein the 2,6-dichloro-5-fluoro- N -{[4-methyl-2-(propane-2-yl)pyridin-3-yl]aminocarbonyl}pyridine-3-carboxamide is mixed with the sodium tert-butoxide in a solvent, wherein the solvent contains 2-methyltetrahydrofuran.

The method of claim 16, wherein the temperature of the solvent is maintained at 5-10°C during mixing and then warmed to 23°C and stirred for 3 hours.

A method for preparing a composition having formula 4a,

The method comprises reacting a compound having the formula 4 in the presence of 2-methyltetrahydrofuran

Mixed with a compound of formula B1

To form the composition having formula 4a.

The method of claim 18, wherein 1.0 molar equivalent of the compound of formula 4 is mixed with 2.0 molar equivalent of the compound of formula B1.

The method of claim 18 or 19, wherein the compound having formula 4 is mixed with the compound having formula B1 in a solvent, wherein the solvent comprises 2-methyltetrahydrofuran and heptane.

A method for preparing a compound of formula 5M,

The method comprises making a composition having formula 4a

Mixing with a base to form the compound of formula 5M.

The method of claim 21, wherein the base is Na ₂ HPO ₄ .

The method of claim 21, wherein the base is NaHCO ₃ .

The method of claim 21, wherein 1.0 molar equivalent of the composition of formula 4a is mixed with 2.0 molar equivalent of the base.

A method as claimed in any one of claims 21 to 24, wherein the composition of formula 4a is mixed with the base in a solvent, wherein the solvent comprises methyl tert-butyl ether and water.

The method of claim 14, further comprising using the compound of formula 4 to prepare a compound of formula 9 or a pharmaceutically acceptable salt thereof,

The method comprises mixing the compound of formula 4 with POCl ₃ and N,N-diisopropylethylamine to form 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one.

The method of claim 26, wherein 1 molar equivalent of the compound of formula 4 is mixed with 1.2 molar equivalents of POCl ₃ .

The method of claim 26, wherein 1 molar equivalent of the compound of formula 4 is mixed with 2.0 molar equivalents of the N,N-diisopropylethylamine.

The method of any one of claims 26 to 28, wherein the compound of formula 4, the POCl ₃ and the N,N-diisopropylethylamine are mixed in a solvent, wherein the solvent comprises toluene.

The method of any one of claims 26 to 28, wherein the compound of formula 4 is substantially stereoisomerically pure 7-chloro-6-fluoro-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidine-2,4(1 H ,3 H )-dione.

The method of claim 26, further comprising reacting the 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one with ( 3S )-3-methylpiperidin-

-1-carboxylic acid tributyl ester and N,N-diisopropylethylamine were mixed to form ( 3S )-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1- Tributyl carboxylate.

The method of claim 31, wherein 1 molar equivalent of the 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one is reacted with 1.1 molar equivalents of the ( 3S )-3-methylpiperidin-

-1-Tributyl formate mixed.

The method of claim 31, wherein 1 molar equivalent of the 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one is mixed with 1.0 molar equivalent of the N,N-diisopropylethylamine.

The method of any one of claims 31 to 33, wherein the 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one, the ( 3S )-3-methylpiperidin-

-1-tert-butyl carboxylate and the N,N-diisopropylethylamine are mixed in a solvent, wherein the solvent contains toluene.

The method of any one of claims 31 to 33, wherein the 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one is substantially stereoisomerically pure 4,7-dichloro-6-fluoro-(1 M )-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one.

The method of claim 31, further comprising mixing the ( 3S )-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1-carboxylic acid tributyl ester, potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium acetate to form ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin-

-1- Tributyl carboxylate .

The method of claim 36, wherein 1.0 molar equivalent of the ( 3S )-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1- Tributyl carboxylate is mixed with 1.2 molar equivalents of potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate.

-1- Tributyl carboxylate was mixed with 0.01 molar equivalent of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

-1- Tributyl carboxylate was mixed with 5.0 molar equivalents of the potassium acetate.

The method of claim 36, wherein the ( 3S )-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1- tert-butyl carboxylate, the potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate, the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and the potassium acetate are mixed in a solvent, wherein the solvent contains dioxane.

The method of any one of claims 36 to 40, wherein the ( 3S )-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1-carboxylic acid tributyl ester is a substantially stereoisomerically pure (3 S )-4-{7-chloro-6-fluoro-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1- Tributyl carboxylate.

The method of claim 36, further comprising mixing the ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1-carboxylic acid tributyl ester and trifluoroacetic acid to form 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin

-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one.

The method of claim 42, wherein the ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1- Tributyl carboxylate and the trifluoroacetic acid are mixed in a solvent, wherein the solvent contains dichloromethane.

The method of claim 42 or 43, wherein the ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1-carboxylic acid tributyl ester is a substantially stereoisomerically pure (3 S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1- Tributyl carboxylate .

The method of claim 42, further comprising subjecting the 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin

6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2( 1H )-one was mixed with acrylyl chloride to form 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[( 2S )-2-methyl-4-(prop-2-enyl)piperidin-2(1H)-one.

-1-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one.

The method of claim 45, wherein 1.0 molar equivalent of the 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin

-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one was mixed with 1.3 molar equivalents of the acrylyl chloride.

The method of claim 45, wherein the 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin

-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2( 1H )-one and the acrylyl chloride are mixed in a solvent, wherein the solvent contains N-methylpyrrolidone.

The method of any one of claims 45 to 47, wherein the 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin

6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2 S )-2-methylpiperidin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one is a substantially stereoisomerically pure 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2 S )-2-methylpiperidin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one.

-1-yl]-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one.

The method of claim 21, further comprising using a compound of formula 5M to prepare a compound of formula 9 or a pharmaceutically acceptable salt thereof,

The method includes mixing 7-chloro-6-fluoro-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidine-2,4(1 H ,3 H )-dione with POCl ₃ and N,N-diisopropylethylamine to form 4,7-dichloro-6-fluoro-(1 M )-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1 H )-one.

The method of claim 49, further comprising reacting 4,7-dichloro-6-fluoro-(1 M )-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidin-2( 1H )-one with (3 S )-3-methylpiperidin-

-1-carboxylic acid tributyl ester and N,N-diisopropylethylamine were mixed to form ( 3S )-4-{7-chloro-6-fluoro-( 1M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1- Tributyl carboxylate.

The method of claim 50, further comprising: ( 3S )-4-{7-chloro-6-fluoro-( 1M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1-carboxylic acid tributyl ester, potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium acetate were mixed to form ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-( 1M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin-

-1- Tributyl carboxylate .

The method of claim 51 further comprises the step of: ( 3S )-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-( 1M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3- d ]pyrimidin-4-yl}-3-methylpiperidin

-1-carboxylic acid tributyl ester was mixed with trifluoroacetic acid to form 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin

The method of claim 52, further comprising subjecting 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[( 2S )-2-methylpiperidin

-1-yl]-(1 M )-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3- d ]pyrimidin-2(1 H )-one is mixed with acrylyl chloride to form the compound of formula 9.